Thermal modulation of an inhalable medicament

ABSTRACT

A thermally modulating inhalable medicament delivery device may deliver an inhalable medicament as an aerosol, vapor, or partial aerosol and partial vapor mixture. The inhalable medicament may be delivered to a target in a subject. Described herein are devices, systems, and methods for delivering an inhalable medicament to a subject.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/424,459, filed on May 28, 2019 and titled THERMAL MODULATION OF ANINHALABLE MEDICAMENT (“the '459 application”), which issued as U.S. Pat.No. 10,737,042 on Aug. 11, 2020, which is a continuation-in-part of U.S.patent application Ser. No. 14/835,595, filed on Aug. 25, 2015 andtitled THERMAL MODULATION OF AN INHALABLE MEDICAMENT, which issued asU.S. Pat. No. 10,300,228 on May 28, 2019 (“the '595 application”). The'595 application included claims for the benefit of priority pursuant to35 U.S.C. § 119(e) to the Jul. 1, 2015 filing date of U.S. ProvisionalPatent Application No. 62/187,289, titled THERMAL MODULATION OF ANINHALABLE MEDICAMENT, the Aug. 26, 2014 filing date of U.S. ProvisionalPatent Application No. 62/042,224, titled INHALABLE DRUG DELIVERYDEVICE—RELATED SYSTEMS, METHODS, FORMULATIONS, AND APPARATUS, the Oct.8, 2014 filing date of U.S. Provisional Patent Application No.62/061,669, titled THERMAL MODULATING INHALABLE MEDICAMENT DELIVERYSYSTEM, and the Oct. 9, 2014 filing date of U.S. Provisional PatentApplication No. 62/061,956, titled THERMAL MODULATING INHALABLEMEDICAMENT DELIVERY SYSTEM. The entire disclosures of all of theforegoing are hereby incorporated herein for all purposes.

RELATED ART

Medicaments may be delivered in an inhalable formulation to treat avariety of medical conditions and symptoms. Such inhalable medicamentformulations may be delivered directly to the lungs. Additionally, aninhalable medicament may be delivered systemically via delivery of theinhalable medicament to the pulmonary vascular system.

A handheld device that can controllably and effectively deliver aninhalable medicament to a target tissue in a subject would beadvantageous in, for example, treating a variety of medical conditionsand symptoms, and for delivery of a medicament systemically.

SUMMARY

Described herein are systems, devices, and methods for delivering aninhalable medicament to a targeted location within the respiratorysystem of a subject. The handheld inhalable medicament delivery devicesdescribed herein are configured to thermally modulate an inhalablemedicament that is contained therein. Thermal modulation optimizes thedroplet size of the inhalable medicament, wherein, typically, the higherthe temperature (up to a threshold), the smaller the average drop sizeof an inhalable medicament. Also typically, the smaller the average dropsize of an inhalable medicament, the further the inhalable medicamentwill travel through the respiratory tract. Therefore, making the dropsizes of an inhalable medicament smaller, for example, by heating themwithin the device, will cause the inhalable medicament to travel furtheralong the respiratory tract of a subject than if the average dropletsize was larger. The relationship of heating, to change in droplet size,to distance travelled within the respiratory tract, may be quantified sothat the relationship is a predictable one. In this way, by controllingthe droplet size of an inhalable medicament through thermal modulation,the devices and methods described herein determine the location in therespiratory tract where the inhalable medicament is primarily delivered.

In an embodiment of the medicament delivery device described herein, aninhaled medicament delivery device comprises a housing to receive acartridge holding a liquid medicament in a reservoir. The cartridgeincludes a penetrable seal that retains the medicament inside thereservoir.

The housing may contain a hollow slideable reservoir tap within it,where the reservoir tap is configured to controllably advance forward topenetrate the seal of an attached cartridge.

The cartridge may be pressurized and further contain a compressedpropellant gas. Once the penetrable seal is penetrated by the reservoirtap, the pressure difference between the pressurized cartridge and thehollow interior of the penetrating reservoir tap causes the propellantto expand and thereby eject the inhalable medicament into the reservoirtap, forming an aerosol.

The reservoir tap may be controllably retracted to stop the flow of theinhalable medicament out of the reservoir via the reservoir tap.

The seal of the device may comprise a self-sealing material.

The reservoir tap may comprise one or more ports that create acommunication from the hollow interior of the reservoir tap to outsideof the reservoir tap. The one or more ports are positioned on thereservoir tap so that one or more of the ports may enter the cartridgewhen the reservoir tap penetrates the cartridge seal. One or more portsmay alternatively or additionally be positioned so that the ports arecovered by the cartridge seal, either when the reservoir tap is drawnback after entering the cartridge or when the reservoir tap penetratesthe cartridge.

When a port enters the cartridge, medicament is propelled through theport into the hollow interior of the reservoir tap. When the reservoirtap is drawn back from the interior of the cartridge, the seal may coveror block the port so that medicament is not able to enter the port, andthus is not able to further enter into the hollow portion of thereservoir tap.

The reservoir tap may include a first port and a second port that havedifferent sizes. The different sizes of said first port and said secondport can be configured to determine a dosing of said medicament. Forexample, in an embodiment where the smaller port is positioned closer tothe tip of the reservoir tap than the larger port, the larger port maybe covered by the seal when the reservoir tap penetrates a certaindistance into the cartridge, thereby releasing a first dose into thehollow interior of the reservoir tap. The larger port may be locatedwithin the interior of the cartridge when the reservoir tap penetratesfurther into the cartridge, thereby releasing a second dose into thehollow interior of the reservoir tap, wherein the second dose is largerthan the first dose.

Whether the medicament is to flow out of the reservoir via both thefirst port and the second port determines a flow rate for saidmedicament out of said reservoir.

In an embodiment, a device for delivering an inhalable medicament mayfurther comprise an air flow amplifier that increases the flow of theinhalable medicament and/or air in the medicament mixture.

Also described herein is a cartridge for use with a device fordelivering an inhalable medicament. A cartridge containing a liquidmedicament may comprise a reservoir that retains the liquid medicamentin a fixed position within the cartridge. The cartridge may furthercomprise a penetrable seal and a compressed propellant. The reservoirmaintains the position of the liquid medicament between the compressedpropellant and the seal, so that the compressed propellant is alwaysbehind the liquid medicament relative to the seal no matter the positionof the cartridge.

The cartridge is configured to couple with a housing of a deliverydevice. The cartridge couples with the delivery device in such a waythat the seal is positioned to be penetrated by an extendable reservoirtap of the medicament delivery device. The extendable reservoir tap isconfigured to penetrate the cartridge seal in order to allow themedicament to flow out of the cartridge when reservoir tap is extended.

In another embodiment, the delivery device described herein comprises orcouples with a cartridge containing a reservoir. In an embodiment, areservoir may comprise a bladder that contains a liquid medicament, andwherein the bladder may be compressed by the propellant to force themedicament out of the reservoir when the pressure inside the cartridgedrops due to, for example, penetration of the cartridge seal.

In another embodiment, a reservoir may comprise a hydrophobic porousreservoir. The reservoir holds the medicament within its pores similarto a sponge. When the propellant forcefully expands due to a change inpressure, the propellant passes into the pores of the porous reservoirthereby displacing the medicament out of the reservoir. A propellant maydisplace the medicament out of the porous reservoir so that themedicament is aerosolized.

In an embodiment, the propellant may be dissolved in the medicament.

The propellant may comprise carbon dioxide dissolved in a medicamentthat includes miscible glycerol. The propellant may comprise carbondioxide dissolved in a medicament that includes glycol.

In an embodiment, an inhaled medicament delivery device may furthercomprise an encapsulated neutralizing agent.

In another embodiment, an inhaled medicament delivery device may furthercomprise an absorbent material to render at least one active ingredientin the medicament unusable if said reservoir is breached via a part ofsaid cartridge that is not said seal.

Also described herein is a method of delivering an inhaled medicament,comprising controllably extending a reservoir tap to penetrate a sealretaining a liquid medicament in a reservoir thereby allowing themedicament to flow out of the reservoir via a port in the reservoir tap.The method also includes controllably retracting the reservoir tap tostop the flow out of the reservoir via the reservoir tap by causing theport to become occluded by the cartridge seal.

In an embodiment, the method may further comprise controllably extendingthe reservoir tap a further amount into the container to allow themedicament to flow into a second port that was previously covered by acartridge seal.

Controllably extending a reservoir tap may be initiated in response to,for example, the start of an inhalation cycle.

Controllably extending reservoir tap may allow a gas to flow into thesecond port while the medicament flows into the first port.

Also described herein is a method of providing a medicament to aninhaled medicament delivery device. The method comprises attaching acartridge having a reservoir, a seal holding the medicament in saidreservoir, and a propellant, wherein the medicament is held in saidreservoir by said seal. The method also includes activating the inhaledmedicament delivery device to penetrate the seal with a reservoir tap,and thereby allow the medicament to be propelled out of the reservoir bythe propellant into the hollow interior of the reservoir tap.

The reservoir may comprise a bladder holding the medicament, the bladderbeing compressed by the propellant to force the medicament out of thereservoir. The reservoir may comprise a hydrophobic porous reservoirholding the medicament, where the propellant is to pass into pores ofthe porous reservoir, thereby displacing the medicament out of thereservoir and into the reservoir tap. A propellant that displaces themedicament out of the porous reservoir may cause the medicament toaerosolize.

Also described herein is a method for delivering an inhalable medicamentto a subject, which comprises puncturing a seal on a cartridge, whereinthe cartridge comprises a cartridge interior containing the inhalablemedicament in liquid form. The method also includes forming an aerosolcomprising the inhalable medicament by releasing the inhalablemedicament into a conduit having an interior pressure that is lower thana pressure within the cartridge interior.

The method may further comprise heating the aerosol within the conduitand delivering the inhalable medicament to a subject through theconduit.

The puncturing or breaking of the seal creates a break in the seal thatmay be reversible and/or re-sealable.

The inhalable medicament may comprise an excipient.

The temperature of an aerosol may be modulated within the conduit intowhich the aerosol is delivered from the cartridge.

An aerosol may comprise particles having a Mass Median AerodynamicDiameter (MMAD) of between 0.1 μm and 15 μm. An aerosol may compriseparticles having a MMAD of 0.1 and 2 μm. As described herein, aninhalable medicament may be delivered into the respiratory orcirculatory system of a subject. The average droplet size of aninhalable medicament comprising an aerosol typically will determine howfar it will travel, or whether it will be expelled.

Described herein is a method of delivering an inhalable medicament to atarget site of a subject, comprising forming an aerosol, which comprisesa plurality of droplets of the inhalable medicament. The method alsoincludes modulating a selectable temperature of the aerosol, wherein thetemperature is selected to modify a size of at least one droplet of theplurality of droplets of the inhalable medicament. The method alsoincludes delivering the temperature modulated aerosol to a subject.Wherein the size of at least one droplet of the plurality of dropletsmay be modified to be smaller than a size that will deposit in a targetsite. The size of at least one droplet of the plurality of droplets ofthe inhalable medicament may be modified to a size that causespharyngeal or tracheal stimulation. The size of the at least one dropletof the plurality of droplets of the inhalable medicament may cause theat least one droplet of the plurality of droplets to be deposited in amouth of a subject. The size of the at least one droplet of theplurality of droplets of the inhalable medicament may cause the at leastone droplet of the plurality of droplets to be deposited in a trachea ofa subject. The size of the at least one droplet of the plurality ofdroplets of the inhalable medicament causes the at least one droplet ofthe plurality of droplets to be deposited in an oropharynx of a subject.The size of the at least one droplet of the plurality of droplets of theinhalable medicament causes the at least one droplet of the plurality ofdroplets to be deposited in a lung of a subject. The size of the atleast one droplet of the plurality of droplets of the inhalablemedicament causes the at least one droplet of the plurality of dropletsto be delivered to one or more lung lobes of a subject. The size of theat least one droplet of the plurality of droplets of the inhalablemedicament causes the at least one droplet of the plurality of dropletsto be delivered to a middle lung lobe of a subject. The size of the atleast one droplet of the plurality of droplets of the inhalablemedicament causes the at least one droplet of the plurality of dropletsto be delivered to an inferior lung lobe of a subject.

The delivered aerosol may be flavored.

The aerosol may be delivered by way of a handheld device. The device maybe configured to be integrated with a ventilator. As the device isorientation-independent it allows for downstream integration of thedevice regardless of patients orientation (elevated, supine, sitting,etc.).

Also described herein is an inhaled medicament delivery device,comprising a housing to receive a cartridge holding a liquid medicamentin a reservoir, the cartridge including a seal that retains saidmedicament in said reservoir, and an extendable reservoir tap, thereservoir tap to controllably extend to penetrate the seal and allow themedicament to flow out of the reservoir via the reservoir tap and tocontrollably retract to stop said flow out of the reservoir via thereservoir tap.

In an embodiment, said seal is comprised of a self-sealing material. Inan embodiment, said reservoir tap includes at least one port that is notoccluded by the seal when the reservoir tap is extended to allow themedicament to flow out of the reservoir via the reservoir tap. In anembodiment, said at least one port is occluded by the seal when thereservoir tap is retracted to stop said flow out of the reservoir viathe reservoir tap. In an embodiment, said reservoir tap includes a firstport and a second port that have different sizes, a controllableextension of the reservoir tap determining whether the medicament is toflow out of the reservoir via the first port and not the second port andwhether the medicament is to flow out of the reservoir via both thefirst port and the second port. In an embodiment, the different sizes ofsaid first port and said second port determine a dosing of saidmedicament. In an embodiment, whether the medicament is to flow out ofthe reservoir via both the first port and the second port determines aflow rate for said medicament out of said reservoir. In an embodiment,the device further comprises an air flow amplifier to receive a firstflow of said propellant to produce a second flow of air and propellantthat is greater than said first flow.

Described herein is a method of delivering an inhaled medicament,comprising controllably extending a reservoir tap to penetrate a sealretaining a liquid medicament in a reservoir, thereby allowing themedicament to flow out of the reservoir via the reservoir tap, andcontrollably retracting the reservoir tap to stop the flow out of thereservoir via the reservoir tap. In an embodiment, the reservoir tapincludes a first port and a second port and the reservoir tap isextended an amount that allows the medicament to flow into the firstport and not to flow into the second port. In an embodiment, the methodfurther comprises controllably extending the reservoir tap a furtheramount to allow the medicament to flow into the second port. In anembodiment, said controllably extending is initiated in response to abeginning of an inhaled cycle. In an embodiment, the method furthercomprises controllably extending the reservoir tap to allow a gas toflow into the second port while the medicament flows into the firstport.

Described herein is an inhaled medicament delivery device, comprising aninterface to releasably attach to a canister holding a liquid medicamentin a reservoir, the canister including a seal that retains saidmedicament in said reservoir, and a hollow member to be activated toextend to a first extension within said canister, pierce the seal, andreceive a flow of the medicament, the hollow member also to bedeactivated to retract and stop the flow. In an embodiment, the hollowmember is activated by electromagnetic force. In an embodiment, thehollow member is deactivated by a return spring. In an embodiment, whensaid hollow member is activated to a second extension within saidcanister, the hollow member receives a flow of a propellant. In anembodiment, said canister comprises the reservoir and a propellantcavity. In an embodiment, when said hollow member is activated to thefirst extension within said canister, a first port in the hollow memberreceives a flow of a propellant from the propellant cavity and a secondport in the hollow member receives the flow of medicament from thereservoir. In an embodiment, when said hollow member is activated to asecond extension within said canister, a first port in the hollow memberreceives a flow of a propellant from the propellant cavity and a secondport in the hollow member is occluded to prevent the flow of medicamentinto the hollow member.

Described herein is a cartridge holding a liquid medicament, comprisinga reservoir holding the liquid medicament, a housing configured toattach to a medicament delivery device, and a seal to retain themedicament in the reservoir, the housing holding the seal, the sealpositioned to be penetrated by an extendable reservoir tap of themedicament delivery device, the extendable reservoir tap to allow themedicament to flow out of the reservoir when extended, and the seal toprevent the medicament from flowing out of the reservoir when theextendable reservoir tap is retracted. In an embodiment, the seal iscomprised of a self-sealing material. In an embodiment, the extendablereservoir tap includes a first port and a second port to receiveliquids, the seal to occlude the second port when the extendablereservoir tap is extended so that the second port does not pass a flowof the medicament. In an embodiment, the first port and the second porthave different sizes, and a dimension of the seal is to determinewhether the medicament is to flow out of the reservoir via the firstport and not the second port or whether the medicament is to flow out ofthe reservoir via both the first port and the second port. In anembodiment, the different sizes of the first port and the second portare to determine a dosing of the medicament. In an embodiment, theocclusion of the second port is to determine a dosing of the medicament.In an embodiment, whether the second port is occluded by said seal is todetermine a flow rate of said medicament out of said reservoir.

Described herein is a method of delivering an inhaled medicament,comprising receiving a controllably extended reservoir tap thatpenetrates a cartridge seal retaining a liquid medicament in a cartridgereservoir thereby allowing the medicament to flow out of the reservoirvia the reservoir tap, and in response to a controlled retraction of thereservoir tap, stopping the flow out of the reservoir via the reservoirtap. In an embodiment, the reservoir tap includes a first port and asecond port and the reservoir tap is extended an amount that allows themedicament to flow into the first port and not into the second port. Inan embodiment, the method further comprises: receiving the reservoir tapwhen extended to a further amount that allows the medicament to flowinto the second port. In an embodiment, the reservoir tap iscontrollably extended in response to a beginning of an inhalation cycle.In an embodiment, the cartridge is configured to allow a gas to flowinto the second port while the medicament flows into the first port. Inan embodiment, the method further comprises receiving a furtherextension of the reservoir tap that allows the medicament to flow intothe first port while the gas flows into the second port.

Described herein is a cartridge for an inhaled medicament deliverydevice, comprising a canister holding a liquid medicament in areservoir, the canister including a seal that retains said medicament insaid reservoir, and an interface to releasably attach to the inhaledmedicament delivery device, the interface configured to receive a hollowmember from the inhaled medicament delivery device when the hollowmember is activated to extend to a first extension within said canister,pierce the seal, and receive a flow of the medicament, the interfacealso configured to stop the flow of the medicament when the hollowmember is retracted for deactivation. In an embodiment, the hollowmember is activated by electromagnetic force. In an embodiment, thecanister includes a return spring to deactivate the hollow member. In anembodiment, the interface can receive the hollow member when activatedto a second extension within said canister, and when the hollow memberis activated to the second extension, the canister provides the hollowmember with a flow of a propellant. In an embodiment, said canistercomprises the reservoir and a propellant cavity. In an embodiment, whensaid hollow member is activated to the first extension within saidcanister, a first port in the hollow member receives a flow of apropellant from the propellant cavity, and a second port in the hollowmember receives the flow of medicament from the reservoir. In anembodiment, when said hollow member is activated to a second extensionwithin said canister, a first port in the hollow member receives a flowof a propellant from the propellant cavity, and a second port in thehollow member is occluded by the cartridge to prevent the flow ofmedicament into the hollow member.

Described herein is an inhaled medicament delivery device, comprising ahousing to receive a cartridge holding a liquid medicament in areservoir, the cartridge including a seal and a propellant, and areservoir tap, the reservoir tap to penetrate the seal and allow themedicament to be propelled out of the reservoir by the propellant andvia the reservoir tap. In an embodiment, the reservoir comprises abladder holding the medicament, the bladder compressed by the propellantto force the medicament out of the reservoir. In an embodiment, thereservoir comprises a hydrophobic porous reservoir holding themedicament, the propellant to pass into pores of the porous reservoir,thereby displacing the medicament out of the reservoir. In anembodiment, as the propellant displaces the medicament out of the porousreservoir, the medicament is aerosolized. In an embodiment, thepropellant is dissolved in the medicament. In an embodiment, thepropellant includes carbon dioxide dissolved in a medicament thatincludes miscible glycerol. In an embodiment, the propellant includescarbon dioxide dissolved in a medicament that includes glycol. In anembodiment, the device further comprises an encapsulated neutralizingagent. In an embodiment, the device further comprises an absorbentmaterial to render at least one active ingredient in the medicamentunusable if said reservoir is breached via a part of said cartridge thatis not said seal.

Described herein is a method of providing a medicament to an inhaledmedicament delivery device, comprising attaching a cartridge having areservoir, a seal holding the medicament in said reservoir, and apropellant, the medicament held in said reservoir by said seal, andactivating the inhaled medicament delivery device to penetrate the sealwith a reservoir tap and allow the medicament to be propelled out of thereservoir by the propellant and via the reservoir tap. In an embodiment,the reservoir comprises a bladder holding the medicament, the bladdercompressed by the propellant to force the medicament out of thereservoir. In an embodiment, the reservoir comprises a hydrophobicporous reservoir holding the medicament, and the propellant is to passinto pores of the porous reservoir, thereby displacing the medicamentout of the reservoir and into the reservoir tap. In an embodiment, asthe propellant displaces the medicament out of the porous reservoir themedicament is aerosolized. In an embodiment, the propellant is dissolvedin the medicament. In an embodiment, the propellant includes carbondioxide dissolved in a medicament that includes miscible glycerol.

Described herein is an inhalable medicament delivery device, comprisingan interface to releasably attach to a cartridge holding a liquidmedicament in a first reservoir and a propellant in a second reservoir,and a hollow member to be activated to extend to a first extension,thereby penetrating a seal and allowing the medicament to be propelled,via the hollow member, out of the first reservoir by a pressure providedby the propellant. In an embodiment, the hollow member is to beactivated to extend to a second extension thereby allowing thepropellant out of the second reservoir via the hollow member. In anembodiment, the first reservoir separates a neutralizing agent from saidliquid medicament. In an embodiment, the hollow member penetrates theseal without releasing the neutralizing agent. In an embodiment, thefirst reservoir comprises a bladder holding the liquid medicament, thebladder compressed by the propellant in the second reservoir to forcethe medicament out of the first reservoir.

Described herein is a cartridge holding a liquid medicament, comprising:a cartridge housing to attach the cartridge to an inhaled medicamentdelivery device; a reservoir holding a liquid medicament; a propellant;and a seal holding the liquid medicament in the reservoir against apressure provided by the propellant, the seal to be controllablypenetrated by a reservoir tap of the inhaled medicament delivery deviceto allow the medicament to be propelled out of the reservoir by thepropellant and via the reservoir tap. In an embodiment, the reservoircomprises a bladder holding the medicament, the bladder compressed bythe propellant to force the medicament out of the reservoir. In anembodiment, the reservoir comprises a hydrophobic porous reservoirholding the medicament, the propellant to pass into pores of the porousreservoir thereby displacing the medicament out of the reservoir. In anembodiment, as the propellant displaces the medicament out of the porousreservoir, the medicament is aerosolized. In an embodiment, thepropellant is dissolved in the medicament. In an embodiment, thepropellant includes carbon dioxide dissolved in a medicament thatincludes miscible glycerol. In an embodiment, the propellant includescarbon dioxide dissolved in a medicament that includes glycol. In anembodiment, the cartridge further comprises an encapsulated neutralizingagent. In an embodiment, the cartridge further comprises an absorbentmaterial to render at least one active ingredient in the medicamentunusable if said reservoir is breached via a part of said cartridge thatis not said seal.

Described herein is a method of providing a medicament to an inhaledmedicament delivery device, comprising attaching a cartridge having areservoir, a seal holding the medicament in said reservoir, and apropellant, the medicament held in said reservoir by said seal, andreceiving a reservoir tap that penetrates the seal to allow themedicament to be propelled out of the reservoir by the propellant andvia the reservoir tap. In an embodiment, the reservoir comprises abladder holding the medicament, the bladder compressed by the propellantto force the medicament out of the reservoir. In an embodiment, thereservoir, comprising a hydrophobic porous reservoir holding themedicament and the propellant, is to pass into pores of the porousreservoir, thereby displacing the medicament out of the reservoir andinto the reservoir tap. In an embodiment, as the propellant displacesthe medicament out of the porous reservoir the medicament isaerosolized. In an embodiment, the propellant is dissolved in themedicament. In an embodiment, the propellant includes carbon dioxidedissolved in a medicament that includes miscible glycerol.

Described herein is a cartridge for an inhalable medicament deliverydevice, comprising: a first reservoir holding a liquid medicament, asecond reservoir holding the propellant, and an interface to releasablyattach to the inhalable medicament delivery device, the interfaceconfigured to receive a hollow member from the inhalable medicamentdelivery device, the hollow member to be activated to extend to a firstextension thereby penetrating a seal of the cartridge and allowing themedicament to be propelled, via the hollow member, out of the firstreservoir by a pressure provided by the propellant. In an embodiment,the interface is configured to allow the hollow member to be activatedto a second extension, thereby allowing the propellant out of the secondreservoir via the hollow member. In an embodiment, the first reservoirseparates a neutralizing agent from said liquid medicament. In anembodiment, the hollow member penetrates the seal without releasing theneutralizing agent. In an embodiment, the first reservoir comprises abladder holding the liquid medicament, the bladder compressed by thepropellant in the second reservoir to force the medicament out of thefirst reservoir.

Described herein is a method for delivering an inhalable medicament to asubject, said method comprising: opening a seal on a cartridge, saidcartridge comprising a cartridge interior, said cartridge interiorcontaining said inhalable medicament in liquid form; forming an aerosolcomprising said inhalable medicament by releasing said inhalablemedicament into a conduit having an interior pressure that is lower thana pressure within said cartridge interior; heating said aerosol withinsaid conduit; and delivering said inhalable medicament to said subjectthrough said conduit. In an embodiment, said inhalable medicamentcomprises an excipient. In an embodiment, said opening the seal forms apassage in the seal that is re-sealable. In an embodiment, said openingthe seal forms a puncture in the seal that is reversible. In anembodiment, a temperature of said aerosol is modulated within saidconduit. In an embodiment, said aerosol comprises particles having aMass Median Aerodynamic Diameter (MMAD) of between 0.5 μm and 5 μm. Inan embodiment, said aerosol comprises particles having a MMAD of 0.1 and2 μm. In an embodiment, said inhalable medicament is delivered to a lungof said subject. In an embodiment, said inhalable medicament isdelivered into the circulatory system of said subject.

Described herein is an inhalable medicament delivery device, comprising:a seal opening member, the seal opening member comprising a firstconduit that is to come into fluid communication with a reservoirinterior that contains the inhalable medicament in liquid form; a nozzlein fluid communication with the first conduit, the nozzle forming anaerosol by releasing the inhalable medicament into a second conduithaving an interior pressure that is lower than a pressure within thereservoir interior; a heater to heat the aerosol within the secondconduit; and a mouthpiece to receive heated aerosol and deliver theheated aerosol to a subject. In an embodiment, after the first conduitcomes into fluid communication with the reservoir interior, the sealopening member is to also deactivate and cut off fluid communicationwith the reservoir interior. In an embodiment, a temperature of saidaerosol is modulated within said second conduit. In an embodiment, saidnozzle produces the aerosol comprising particles having a Mass MedianAerodynamic Diameter (MMAD) of between 0.5 μm and 5 μm. In anembodiment, said nozzle produces the aerosol comprising particles a MMADof 0.1 and 2 μm. In an embodiment, said aerosol is to be delivered to alung of said subject. In an embodiment, said inhalable medicament isdelivered into the circulatory system of said subject.

Described herein is an inhalable medicament container, comprising: areservoir having a reservoir interior, the reservoir interior of themedicament container containing the inhalable medicament in liquid form;a seal configured to prevent the release of the medicament prior to anactivation of a seal opening member, the seal configured to receive theseal opening member in order to release the medicament, the seal openingmember comprising a first conduit that is to come into fluidcommunication with the reservoir interior; and, when activated, the sealopening member to be in fluid communication with a nozzle, the nozzleforming an aerosol by releasing the inhalable medicament into a secondconduit having an interior pressure that is lower than a pressure withinthe reservoir interior, the aerosol to be heated within the secondconduit and delivered to a subject. In an embodiment, after the firstconduit comes into fluid communication with the reservoir interior, theseal opening member is to cooperate with the seal to deactivate and cutoff fluid communication with the reservoir interior. In an embodiment,the container further comprises a propellant to provide the interiorpressure. In an embodiment, the container further comprises a propellantto be mixed with the aerosol.

Described herein is a method of delivering an inhalable medicament to atarget site of a subject, said method comprising: forming an aerosolcomprising a plurality of droplets of said inhalable medicament;modulating a selectable temperature of said aerosol, wherein saidtemperature is selected to modify a size of at least one droplet of saidplurality of droplets of said inhalable medicament; and delivering saidtemperature modulated aerosol to a subject. In an embodiment, said sizeof said at least one droplet of said plurality of droplets is modifiedto be smaller than a size that will deposit in a target site. In anembodiment, said size of said at least one droplet of said plurality ofdroplets of said inhalable medicament is modified to a size that causestracheal stimulation. In an embodiment, said size of said at least onedroplet of said plurality of droplets of said inhalable medicamentcauses said at least one droplet of said plurality of droplets to bedeposited in the mouth of the subject. In an embodiment, said size ofsaid at least one droplet of said plurality of droplets of saidinhalable medicament causes said at least one droplet of said pluralityof droplets to be deposited in the trachea of the subject. In anembodiment, said size of said at least one droplet of said plurality ofdroplets of said inhalable medicament causes said at least one dropletof said plurality of droplets to be deposited in the oropharynx of thesubject. In an embodiment, said size of said at least one droplet ofsaid plurality of droplets of said inhalable medicament causes said atleast one droplet of said plurality of droplets to be deposited in alung of the subject. In an embodiment, said size of said at least onedroplet of said plurality of droplets of said inhalable medicamentcauses said at least one droplet of said plurality of droplets to bedelivered to a superior lung lobe of the subject. In an embodiment, saidsize of said at least one droplet of said plurality of droplets of saidinhalable medicament causes said at least one droplet of said pluralityof droplets to be delivered to a middle lung lobe of the subject. In anembodiment, said size of said at least one droplet of said plurality ofdroplets of said inhalable medicament causes said at least one dropletof said plurality of droplets to be delivered to an inferior lung lobeof the subject. In an embodiment, said aerosol is flavored. In anembodiment, said aerosol is delivered through a handheld device.

Described herein is an inhalable medicament delivery device, comprising:an aerosol generator to form a first aerosol mixture comprising a firstplurality of droplets of an inhalable medicament, the first plurality ofdroplets having a first size distribution; a thermal modulator toreceive the first plurality of droplets and modify said first aerosolmixture to produce a second aerosol mixture comprising a secondplurality of droplets of the inhalable medicament, the second pluralityof droplets having a second size distribution; and a delivery passage toprovide a subject with said second aerosol mixture. In an embodiment,said first aerosol mixture is modified such that said second sizedistribution includes droplets that are to be smaller than a size thatwill deposit in a target site. In an embodiment, said first aerosolmixture is modified such that said second size distribution includesdroplets of a size that causes tracheal stimulation. In an embodiment,said first aerosol mixture is modified such that said second sizedistribution includes droplets of a size that causes droplets to bedeposited in a mouth of the subject. In an embodiment, said size of saidat least one droplet of said plurality of droplets of said inhalablemedicament causes said at least one droplet of said plurality ofdroplets to be deposited in the trachea of the subject. In anembodiment, said size of said at least one droplet of said plurality ofdroplets of said inhalable medicament causes said at least one dropletof said plurality of droplets to be deposited in the oropharynx of thesubject. In an embodiment, said size of said at least one droplet ofsaid plurality of droplets of said inhalable medicament causes said atleast one droplet of said plurality of droplets to be deposited in atarget lobe of a lung of the subject.

Described herein is an inhalable medicament aerosol generator,comprising: a detachable reservoir having a reservoir interior and apropellant, the reservoir interior of the medicament containercontaining the inhalable medicament in liquid form, the propellant toforce the liquid medicament out of the reservoir; an interfaceconfigured to receive the inhalable medicament from the reservoir fordelivery to a subject; an aerosol generator to receive the inhalablemedicament and form a first aerosol mixture comprising the propellantand a first plurality of droplets of the inhalable medicament, the firstplurality of droplets having a first size distribution; a heated conduitto receive the first plurality of droplets and modify said first aerosolmixture to produce a second aerosol mixture comprising a secondplurality of droplets of the inhalable medicament, the second pluralityof droplets having a second size distribution; and a delivery passage toprovide a subject with the second aerosol mixture. In an embodiment,said first aerosol mixture is modified such that said second sizedistribution includes droplets that are to be smaller than a size thatwill deposit in a target site.

Described herein is a method for delivering an inhalable medicament to asubject, said method comprising: receiving a seal opening member toplace a first conduit into fluid communication with the contents of areservoir, the contents of the reservoir including the inhalablemedicament in liquid form, and providing the inhalable medicament to anaerosol generator via the first conduit, the aerosol generator formingan aerosol by releasing the inhalable medicament into a second conduithaving an interior pressure that is lower than a pressure within thereservoir, the aerosol to be heated in the second conduit to form aheated aerosol, and the heated aerosol to be delivered to a subject. Inan embodiment, said inhalable medicament comprises an excipient. In anembodiment, the seal opening member is repositioned to stop the fluidcommunication of the contents of the reservoir and the first conduit. Inan embodiment, the seal opening member forms a puncture in a seal thatis reversible. In an embodiment, a temperature of said aerosol ismodulated within said second conduit. In an embodiment, said aerosolcomprises particles having a Mass Median Aerodynamic Diameter (MMAD) upto 5 μm. In an embodiment, said aerosol comprises particles having aMMAD up to 2 In an embodiment, said inhalable medicament is delivered toa lung of said subject. In an embodiment, said inhalable medicament isdelivered into a circulatory system of said subject.

Described herein is an inhalable medicament reservoir, comprising: areservoir having a reservoir interior holding an inhalable medicament inliquid form, the reservoir to provide the inhalable medicament to anaerosol-generating device, the aerosol-generating device to provide aseal opening member to open a seal of said reservoir and to provide afirst conduit of the aerosol-generating device with the inhalablemedicament for delivery to a nozzle in fluid communication with thefirst conduit, the nozzle forming a heated aerosol internal to theaerosol-generating device by releasing the inhalable medicament into asecond conduit that is heated and also has an interior pressure that islower that a pressure within the reservoir interior, and an interface toattach to the aerosol-generating device and to receive the seal openingmember, the interface to include a conduit closing member to interfacewith the seal opening member to close the first conduit, such that thereservoir interior is not in fluid communication with theaerosol-generating device and the production of the heated aerosol isstopped. In an embodiment, after the first conduit is provided with theinhalable medicament for delivery to the nozzle, the seal opening memberis to also deactivate and stop the production of the heated aerosol. Inan embodiment, a temperature of said heated aerosol is to be modulatedwithin said second conduit. In an embodiment, said nozzle produces theaerosol comprising particles having a Mass Median Aerodynamic Diameter(MMAD) of between 0.5 μm and 5 μm. In an embodiment, said nozzleproduces the aerosol comprising particles a MMAD of 0.1 and 2 μm. In anembodiment, said aerosol is to be delivered to a lung of said subject.In an embodiment, said inhalable medicament is delivered into acirculatory system of said subject.

Described herein is an inhalable medicament container, comprising: areservoir having a reservoir interior, the reservoir interior of themedicament container containing the inhalable medicament in liquid form;a seal configured to prevent the release of the medicament prior to anactivation of a seal opening member, the seal configured to receive theseal opening member in order to release the medicament, the seal openingmember comprising a first conduit that is to come into fluidcommunication with the reservoir interior; and, when activated, the sealopening member to be in fluid communication with a nozzle, the nozzleforming an aerosol by releasing the inhalable medicament into a secondconduit having an interior pressure that is lower that a pressure withinthe reservoir interior, the aerosol to be heated within the secondconduit and delivered to a subject. In an embodiment, after the firstconduit comes into fluid communication with the reservoir interior, theseal opening member is to cooperate with the seal to deactivate and cutoff fluid communication with the reservoir interior. In an embodiment,the container further comprises a propellant to provide the interiorpressure. In an embodiment, the container further comprises a propellantto be mixed with the aerosol.

Described herein is a method of delivering an inhalable medicament,comprising: interfacing with an aerosol generator having a firstconduit; engaging the first conduit to place the first conduit in fluidcommunication with the contents of a reservoir, the contents of thereservoir including the inhalable medicament in liquid form; andproviding the inhalable medicament to the first conduit of the aerosolgenerator under pressure from a propellant, the pressure from thepropellant causing the aerosol generator to form an aerosol comprising aplurality of droplets of said inhalable medicament, the propellant alsocausing a flow of said plurality of droplets through a selectabletemperature conduit that is to modify a size of at least one droplet ofsaid plurality of droplets of said inhalable medicament and is todeliver a temperature modulated aerosol to a subject. In an embodiment,said size of said at least one droplet of said plurality of droplets ismodified to be smaller than a size that will deposit in a target site.In an embodiment, said size of said at least one droplet of saidplurality of droplets of said inhalable medicament is modified to a sizethat causes tracheal stimulation. In an embodiment, said size of said atleast one droplet of said plurality of droplets of said inhalablemedicament causes said at least one droplet of said plurality ofdroplets to be deposited in the mouth of the subject. In an embodiment,said size of said at least one droplet of said plurality of droplets ofsaid inhalable medicament causes said at least one droplet of saidplurality of droplets to be deposited in the trachea of the subject. Inan embodiment, said size of said at least one droplet of said pluralityof droplets of said inhalable medicament causes said at least onedroplet of said plurality of droplets to be deposited in the oropharynxof the subject. In an embodiment, said size of said at least one dropletof said plurality of droplets of said inhalable medicament causes saidat least one droplet of said plurality of droplets to be deposited in alung of the subject. In an embodiment, said aerosol comprises particleshaving a Mass Median Aerodynamic Diameter (MMAD) up to 5 μm. In anembodiment, said aerosol is flavored.

Described herein is an inhalable medicament reservoir, comprising apropellant and a reservoir having a reservoir interior holding aninhalable medicament in liquid form, the reservoir to provide theinhalable medicament to an aerosol-generating device, theaerosol-generating device to provide a seal opening member to open aseal of said reservoir and to provide a first conduit of theaerosol-generating device with the inhalable medicament for delivery to,under flow provided by the propellant, a nozzle in fluid communicationwith the first conduit, the nozzle forming a first aerosol mixturecomprising a first plurality of droplets of the inhalable medicament,the first plurality of droplets having a first size distribution, theflow provided by the propellant to also move the first plurality ofdroplets into a thermal modulator where said first aerosol mixture ismodified to produce a second aerosol mixture comprising a secondplurality of droplets of the inhalable medicament, the second pluralityof droplets having a second size distribution, the flow provided by thepropellant to also aid in the delivery of the second aerosol mixture toa subject. In an embodiment, said first aerosol mixture is modified suchthat said second size distribution includes droplets that are to besmaller than a size that will deposit in a target site. In anembodiment, said first aerosol mixture is modified such that said secondsize distribution includes droplets of a size that causes trachealstimulation. In an embodiment, said first aerosol mixture is modifiedsuch that said second size distribution includes droplets of a size thatcauses droplets to be deposited in the mouth of the subject. In anembodiment, said size of said at least one droplet of said plurality ofdroplets of said inhalable medicament causes said at least one dropletof said plurality of droplets to be deposited in the trachea of thesubject. In an embodiment, said size of said at least one droplet ofsaid plurality of droplets of said inhalable medicament causes said atleast one droplet of said plurality of droplets to be deposited in theoropharynx of the subject. In an embodiment, said size of said at leastone droplet of said plurality of droplets of said inhalable medicamentcauses said at least one droplet of said plurality of droplets to bedeposited in a target lobe of a lung of the subject.

Described herein is an inhalable medicament container, comprising: areservoir having a reservoir interior, the reservoir interior of themedicament container containing the inhalable medicament in liquid form;a propellant to force the liquid medicament out of the reservoir; and,an interface configured to deliver the inhalable medicament from thereservoir to a delivery device for delivery to a subject, the deliverydevice having an aerosol generator to form a first aerosol mixturecomprising the propellant and a first plurality of droplets of theinhalable medicament, the first plurality of droplets having a firstsize distribution, the delivery device also having a thermal modulatorto receive the first plurality of droplets and to modify said firstaerosol mixture to produce a second aerosol mixture comprising a secondplurality of droplets of the inhalable medicament, the second pluralityof droplets having a second size distribution, the delivery device alsohaving a delivery passage to provide a subject with said second aerosolmixture. In an embodiment, said second aerosol mixture is modified intoa third aerosol mixture while in the oropharynx region, the thirdplurality of droplets having a third size distribution. In anembodiment, said second aerosol mixture is modified into a third aerosolmixture while in the lung airways region, the third plurality ofdroplets having a third size distribution.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1A illustrates the pulmonary delivery of an inhaled medicament.

FIG. 1B illustrates an evolution of a vapor-aerosol mix duringinhalation.

FIG. 2A is an illustration of thermal modulation and aerosol-vaporevolution during inhalation of a vapor-aerosol mix.

FIG. 2B is an illustration of air-mixture and thermal modulation.

FIG. 2C is an illustration of a preheated air-mixture and thermalmodulation.

FIG. 3A is an illustration of a medicament cartridge and reservoir tapfor an inhaled medicament delivery device.

FIG. 3B is an illustration of the functioning of a reservoir tap of aninhaled medicament delivery device.

FIG. 3C is an illustration of a tamper-resistant medicament cartridgeand a reservoir tap for an inhaled medicament delivery device.

FIG. 3D is an illustration of the neutralization of medicament by atamper-resistant cartridge.

FIG. 4A is an illustration the operation of a medicament cartridge withmedicament bladder.

FIG. 4B is an illustration the operation of a tamper-resistantmedicament cartridge.

FIG. 5A is an illustration of a reservoir and reservoir tap positionedto provide a first medicament dosing/mixture.

FIG. 5B is an illustration of a reservoir and reservoir tap positionedto provide a second medicament dosing/mixture.

FIG. 5C is an illustration of a cartridge configured to control amedicament dosing/mixture.

FIGS. 6A-6C illustrate the actuation of a reservoir tap.

FIG. 7 illustrates controlled thermal heating of a reservoir tap.

FIG. 8 is a chart illustrating medicament flow rate.

FIG. 9A is an illustration of a medicament cartridge with a reservoirand propellant tap for an inhaled medicament delivery device.

FIG. 9B is an enlarged illustration of a medicament cartridge withreservoir and propellant tap for an inhaled medicament delivery device.

FIG. 9C is an illustration of the activation of a medicament cartridgewith reservoir and propellant tap.

FIG. 10A is an isometric exterior view of an inhalable medicamentdelivery device.

FIG. 10B illustrates an isometric exploded view of an inhalablemedicament delivery device.

FIG. 10C illustrates an isometric exploded view of a cartridge cover andcartridge for an inhalable medicament delivery device.

FIG. 10D illustrates an isometric exploded view of a cartridge for aninhalable medicament delivery device.

FIGS. 10E and 10F illustrate an exploded view of an embodiment of areservoir tap assembly for an inhalable medicament delivery device.

FIG. 10G illustrates an exploded view of an embodiment of a valveassembly for an inhalable medicament delivery device.

FIG. 10H illustrates an exploded view of an embodiment of a battery andelectronics assembly for an inhalable medicament delivery device.

FIG. 11 illustrates an isometric exploded view of a cartridge for aninhalable medicament delivery device.

FIG. 12 illustrates an isometric exploded view of an inhalablemedicament delivery device.

FIG. 13 is a block diagram of a computer system.

DETAILED DESCRIPTION

Before describing the subject matter disclosed herein in detail, it isto be understood that the subject matter is not limited in itsapplication to the details of construction, experiments, exemplary data,and/or the arrangement of the components set forth in the followingdescription or illustrated in the drawings. The subject matter describedherein is capable of other variations, and therefore the variationsdescribed herein should not be taken to limit the scope of the subjectmatter of the description in any way. Also, it is to be understood thatthe phraseology and terminology employed herein is for purpose ofdescription only and should not be regarded as limiting in any way. Inthe following detailed description of embodiments of the describedsubject matter, numerous specific details are set forth in order toprovide a more thorough understanding of the inventive concepts.However, it will be apparent to one of ordinary skill in the art thatthe inventive concepts within the disclosure may be practiced withoutthese specific details. In other instances, well-known features have notbeen described in detail to avoid unnecessarily complicating the instantdisclosure.

Further, unless expressly stated to the contrary, “or” refers to aninclusive or and not an exclusive or. For example, a condition A or B issatisfied by any one of the following: A is true (or present) and B isfalse (or not present), A is false (or not present) and B is true (orpresent), and both A and B are true (or present).

In addition, use of the “a” or “an” are employed to describe elementsand components of the embodiments herein. This is done merely forconvenience and to give a general sense of the inventive concepts. Thisdescription should be read to include one or at least one and thesingular also includes the plural unless it is obvious that it is meantotherwise.

The term “subject” as used herein may refer to a human subject or anyanimal subject.

Finally, as used herein, any reference to “one embodiment” or “anembodiment” means that a particular element, feature, structure, orcharacteristic described in connection with the embodiment is includedin at least one embodiment. The appearances of the phrase “in oneembodiment” in various places in the specification are not necessarilyall referring to the same embodiment.

Medicament Delivery Device

The devices and methods described herein may be configured to modify aparticle size, mass, or distribution of an aerosol of an inhalablemedicament in order to deliver the inhalable medicament to a specifictarget within the respiratory tract of a subject. The respiratory tractcomprises upper and lower respiratory tract. The upper respiratory tractgenerally comprises the nose or nostrils, nasal cavity, mouth, throat(pharynx), and voice box (larynx). The lower respiratory tract generallycomprises the trachea (windpipe), bronchial tubes, and lungs. The lungsare further anatomically and functionally divided on the right into anupper, mid, and lower lobes, and upper and lower lobes on the left. Theairways continue to branch from the trachea segmentally until theterminal bronchioles and the alveoli, where gas exchange occurs withcapillary blood. The modification of an average particle or droplet sizeof an inhaled medicament allows the medicament to be targeted to, forexample, the lower lung. Which is to say that medicament is caused totravel through the mouth (or nose), through the oropharynx, through thetrachea, through the bronchi, and into the lung. Medicament may betargeted to any part of the respiratory system by controlling theaverage size of the aerosol particle or droplet size. Generally, thesmaller the aerosol particle or droplet, the farther into therespiratory tract the majority of the quantity of medicament willtravel. However, if an aerosol particle is very small, it will simply beinhaled and subsequently exhaled and the medicament will not bedelivered to any region of the airway.

Delivery of an inhaled medicament to a specific target within therespiratory tract is advantageous in general, because, for example, itdelivers a concentrated dose of a medicament to a target rather thanhaving the dose of medicament disperse throughout the respiratory tract.This is advantageous for treating, for example, a bacterial infection inthe lung by directly delivering a dose of an inhalable antibiotic to theinfected area. Targeted delivery may be advantageous for treating, forexample, a loculated bacterial infection within the lung. In anotherexample, the targeted delivery of a mucolytic in a patient with CysticFibrosis to the small airways, namely the bronchioles and bronchi, wherethe mucous plugging is most prevalent would be advantageous. Likewise,targeted delivery of a chemotherapeutic agent directly to a tumor in therespiratory tract may be achieved. Overall, targeted delivery allows forthe delivery of lower drug loads to patients decreasing the risk andeffects of drug toxicity, drug allergy, and side effects.

Additionally, the devices and methods described herein may be used todeliver a medicament into the circulatory system. Lung tissue comprisesalveoli, which are cells that exchange oxygen and carbon dioxide withthe circulatory system. Rich vascular networks surround the alveoli andare relatively permeable to exchange of gasses and particles. The deviceand method described herein provides a means for delivery of an inhaledmedicament directly into the circulatory system. Namely, the devices andmethods described herein are configured to selectably deliver an inhaledmedicament to the alveoli of the lungs wherein the medicament is passedinto the vascular network that surrounds the alveoli. The vascularnetwork delivers the medicament to the heart through the pulmonary veinsafter which the inhaled medicament enters the systemic circulatorysystem.

Delivery of an inhaled medicament into the circulatory system isadvantageous in general, because, for example, it provides analternative mode of delivery of a medicament directly into thecirculatory system. In contrast, medicaments delivered orally must firstbe digested before entering the circulatory system, which is a slow andunpredictable process. The digestive process causes a relativelyunpredictable loss of dose through differences in gastrointestinalabsorption and metabolism in different subjects (first-pass metabolism).Medicaments delivered intravenously require intravenous access, whichcan be difficult to obtain and predisposes the patient to risk ofinfection and other potential complications. Effective delivery ofmedicament into circulation via the respiratory system is advantageousfor, for example, providing a rapid delivery of medicament directly intothe circulatory system, such as in an emergency situation when an oraldose would take too long and no intravenous access is available.Effective delivery of medicament directly into the circulatory via therespiratory system is also advantageous for, for example, providing ameans for a subject to take a medicament that is only formulated forintravenous delivery at home without requiring long term intravenousaccess or ports such as, for example, certain antibiotics orchemotherapeutic agents.

Described herein is a controllable inhaled medicament delivery deviceconfigured to generate inhalable aerosols, vaporized aerosols, and/orvapor-aerosol mixes. An aerosol particle size may be controlled by thedevice using thermal modulation. Typically, the size of an aerosoldroplet decreases as it is heated.

FIG. 1A shows a schematic representation of the targeted delivery of aninhalable medicament with the delivery device described herein. Theshown target of the medicament delivery is the mid lung. A hand heldinhaled medicament delivery device 110 contains a medicament 120, and isoperated by a subject 130. In the following discussions, the orientationof a device (e.g., inhaled medicament delivery device 110) is referredto in relation to the subject 130, such that the proximal end of theinhaled medicament delivery device 110 is closest to the subject 130during the operation of the inhaled medicament delivery device 110 andthe distal end of the inhaled medicament delivery device 110 lies awayfrom the subject 130.

The inhaled medicament delivery device 110 comprises a housing and amouthpiece. The outer shape of the housing may be formed into any shapeincluding, for example, rectangular, cylindrical, or spheroid. Thosehaving skill in the art will understand that any housing shape issuitable. In a preferred embodiment, the housing is shaped so that it isconveniently held in the hand of a subject 130. For example, in anembodiment, the housing of the inhaled medicament delivery device 110 isan elongate housing, wherein the length of the inhaled medicamentdelivery device 110 is larger than the width of the inhaled medicamentdelivery device 110. In an embodiment, the mouthpiece of the inhaledmedicament delivery device 110 is continuous with the interior of thehousing. In an embodiment, the interior of the mouthpiece is continuouswith a hollow conduit that passes through the interior of the housing. Amouthpiece is typically smaller than the housing. For example, thediameter of a cylindrical mouthpiece is typically smaller than thediameter of a cylindrical housing. Likewise, for example, the width of arectangular mouthpiece is smaller than width of a rectangular housing.It should be understood by those having skill in the art that amouthpiece may also be of the same dimensions as the housing. In anembodiment, the mouthpiece is removably coupled with the housing of theinhaled medicament delivery device 110.

The housing of the inhaled medicament delivery device 110 may comprise ahard plastic or polymer material. In an embodiment, the housing of theinhaled medicament delivery device 110 comprises a metal or glass. In anembodiment, the housing comprises the same material as the housing. Inan embodiment the mouthpiece comprises a material that will not irritatethe mouth or convey an unpleasant sensation, such as, for example, aplastic or a thermoelastic polymer.

In an embodiment, the housing of the inhaled medicament delivery device110 may not connect to a mouthpiece. In an embodiment, the subject 130holds the housing either near or directly in contact with his or hermouth. In an embodiment, the housing is configured to couple withanother conduit such as, for example, a venti mask.

In an embodiment, the housing may be configured to couple with anendotracheal or tracheostomy tube, face tent, breathing mask, or anyother respiratory assistance device. The housing may be configured todirectly couple with an endotracheal or tracheostomy tube, face tent, orbreathing mask, or the housing may couple with adaptors that then couplewith an endotracheal or tracheostomy tube, face tent, or breathing mask.

As shown by notional arrows, a medicament 120 is delivered into theairway of a subject 130 by the inhaled medicament delivery device 110.The medicament 120 travels into the subject's 130 mouth, upper airway132, lower airways 133, and then into the targeted pulmonary parenchyma131. Medicament 120 may be further delivered through the pulmonaryvasculature of a subject 130, and into the systemic vasculature of asubject 130 when the subject 130 uses the inhaled medicament deliverydevice 110. During this progression, the inhaled formulation/mixture maybe deposited (and thereby absorbed) in a region strongly influenced bythe particle size and composition of the mixture.

While FIG. 1A shows an embodiment in which a medicament 120 travels intothe pulmonary parenchyma 131, in other embodiments, the medicament 120is delivered to another specific target. For example, the medicament 120delivery may be targeted to the mouth. For example, the medicament 120delivery may be targeted to the oropharynx. For example, the medicament120 delivery may be targeted to the upper or lower airway. For example,the medicament 120 delivery may be targeted to a region of the lung suchas the upper, mid, or lower lungs. For example, the medicament 120delivery may be targeted to the pulmonary vasculature. Delivery ofmedicament 120 to specific targets is achieved by varying certainproperties of the medicament 120 that is delivered to the subject 130via the inhaled medicament delivery device 110. For example, the inhaledmedicament delivery device 110 may heat an aerosolized medicament beforeit is delivered to a subject 130. Heating the aerosolized medicament 120before it is delivered affects, for example, the aerosol particle size,wherein heating typically decreases the size of the aerosolizedmedicament 120 particles. Aerosol particles that are smaller typicallytravel further into the respiratory tract. For a range of particlesizes, the relationship of the size of the aerosol particle to thedistance traveled through the airway is a direct relationship. However,particles that are smaller than a threshold amount will be exhaledrelatively quickly. Thus, by controlling the size of an aerosol particleby, for example, applying heat to an aerosol, the distance that anaerosol travels may be controlled.

Similarly, for a range of aerosol temperatures, the amount of heat thatis applied has a direct relationship to the amount in which a particlesize is decreased. For this range, the greater the heat that is appliedto an aerosol, the smaller the resulting particle. Outside of thisrange, applying more heat tends to increase particle size. That is, overa particular range of temperatures, the amount of heat applied to anaerosol is directly and predictably related to the size of the aerosolparticle that is ultimately delivered by the inhaled medicament deliverydevice 110 into the airway of the subject 130. In this way, controllingthe amount of heat applied to an aerosol by the inhaled medicamentdelivery device 110 determines how far into the respiratory tract thatan aerosolized medicament 120 travels.

The aerosol generated by the inhaled medicament delivery device 110 may,for example, be moved to travel by a propellant gas. The aerosol may becaused to travel by a pressure differential, caused by, for example, thesubject 130 inhaling the aerosol through an opening in the inhaledmedicament delivery device 110, creating a negative pressuredifferential within the inhaled medicament delivery device 110 and thesubject's 130 airway.

Generally, an inhalable medicament 120 generated by the inhaledmedicament delivery device 110 may be delivered passively, actively, ora combination of both. In passive delivery, delivery may be caused oraided by the subject 130 inhaling or breathing in the medicament 120aerosol. In active delivery, delivery of the inhalable medicament 120may, for example, be delivered, entirely by the inhaled medicamentdelivery device 110, wherein the subject 130 does not aid delivery byinhaling or breathing in the medicament 120. Alternatively, themedicament 120 may be delivered by the combined action of the inhaledmedicament delivery device 110 and the subject 130. For example, theinhaled medicament delivery device 110 may propel the aerosolizedmedicament 120 and the subject 130 may be instructed or caused to breathin the aerosolized medicament 120.

In an embodiment, the medicament 120 is stored in the inhaled medicamentdelivery device 110 as a liquid or viscous formulation.

FIG. 1B shows an evolution of an aerosol during inhalation. In FIG. 1B,a subject 130 inhales, via an inhaled medicament delivery device 110, anaerosol comprising a medicament 120 into their mouth and oropharynx 132.Aerosol typically comprises droplets or particles that have a droplet orparticle size of greater than or equal to 0.01 μm.

An aerosolized medicament may be delivered to a subject having arelatively uniform droplet size or as a mixture of different dropletsizes. In FIG. 1B, an aerosolized mixture 121 is comprised of a firstamount of vapor (shown as wavy lines in FIG. 1B) and a second amount ofaerosol having a second droplet size (shown as small circles in FIG.1B). Depending upon the application, it should be understood that theaerosolized mixture 121 may include no vapor or no aerosol. However, forthe purposes of this discussion, the aerosolized mixture 121 will beconsidered to include both vapor and aerosol droplets. As inhaled, theaerosolized mixture 121 is illustrated in FIG. 1B in the oropharynx 132.While in the region of the mouth and the oropharynx 132, a small amountof the aerosolized mixture 121 may contact the tongue 134. If theaerosolized mixture 121 contains a flavorant, contact with the tongue134 or the oropharynx 132 will provide the subject 130 with a tastesensation.

As the aerosolized mixture 121 flows from the oropharynx 132 to the lungairways region 133, the aerosol and/or vapor properties of theaerosolized mixture 121 evolve (i.e., change). The evolution of theaerosolized mixture 121 may be caused (at least in part) by a cooling orheating of the aerosolized mixture 121 while in the respiratory tract.For example, a temperature change inside the airway of the subject 130may occur as a result of warm or cold ambient air also being inhaled bythe subject 130 with the aerosolized mixture 121. For example, thetemperature change may occur as a result of interaction of theaerosolized mixture 121 with the body temperature of the subject 130.The evolution may be caused (at least in part) by the interaction of theaerosol droplets with each other over time (e.g., coagulation or thecollision of lesser size particles causing the formation of largerparticles).

Because the average droplet size of a vapor typically changes with achange in temperature, the evolution of the aerosolized mixture 121within the airway of the subject 130 is expected to change thecomposition of particles or droplets within the aerosolized mixture 121.That is, after evolution of the aerosolized mixture 121 in oropharynx132, the aerosolized mixture 121 may change to a mixture 122 as ittravels in the region 133. The new mixture 122 in the region 133 iscomprised of an aerosol having a third droplet size.

As mixture 121 evolves while traveling to become mixture 123 in thelungs 131, it should be understood to have a composition that may differfrom the composition of mixtures 121 or 122.

Generally speaking, because the airways and lungs are moist, an averagesize of an aerosol particle, whether in a mixture of aerosol droplets ora homogenous aerosol, is expected to increase as the medicament 120travels through airway. The amount of increase in aerosol particle sizeis further affected by physiologic factors such as, for example, bodytemperature or airway length. The amount of increase in aerosol particlesize is further affected by, for example, the velocity of travel of themedicament 120 aerosol through the airway.

FIG. 2A shows a schematic view of both thermal modulation within aninhaled medicament delivery device 210 and aerosol evolution duringinhalation of an aerosol mixture as it travels through the inhaledmedicament delivery device 210 and through the airway. In the embodimentshown in FIG. 2A, the interior of the inhaled medicament delivery device210 contains four heaters 213-216, but it should be understood that anynumber of heaters, or one single heater, or a heater or a pluralityheaters thermally coupled with the aerosol nozzle, are suitable for usewith the devices and methods described herein.

The inhaled medicament delivery device 210 may comprise an aspirationtube 219 through which the aerosol travels before passing through themouth (or nose) of a subject 230. The inhaled medicament delivery device210 may comprise a nozzle 212 that directs an aerosol into theaspiration tube 219. The inhaled medicament delivery device 210 maycomprise or be coupled to a cartridge 218 that contains a liquid orviscous medicament within a reservoir 220.

The heaters 213-216 may be positioned in various positons relative toother components within the inhaled medicament delivery device 210. Forexample, the heaters 213-216 may be positioned near or surrounding theaspiration tube 219. For example, the heaters 213-216 may positionednear or surrounding the nozzle 212.

In an embodiment, zero, one, or more heaters are positioned near theaspiration tube 219, and zero, one, or more heaters are positioned nearthe nozzle 212. In an embodiment, the heaters 213-216 are positioned sothat they apply heat to the entire circumference of a cylindricalconduit or the entire outer dimensions of a polygonal conduit, such asfor example, the aspiration tube 219. In an embodiment, the heatingelement is positioned to apply heat to only one portion of the surfaceof a conduit.

In an embodiment, the heaters 213-216 comprise a heating element. Aheating element may be made out of any suitable thermal conductingmaterial. For example, a heating element may comprise a conductive metalor metal alloy such as titanium and titanium alloys, nickel or chromium,or nickel and chromium alloys. For example, a heating element maycomprise ceramic. It should be understood that numerous thermalconducting materials are suitable for use with the devices and methodsdescribed herein and the examples provided are not to be taken aslimiting in any way.

In an embodiment, a heating element is activated by an electric currentthat is passed through the element. The inherent resistance of thematerial creates heat when an electric current passes through theelement. The temperature of the heating elements directly relates to theheat emitted by the heating elements and thus the heat emitted by theheaters 213-216. In addition, the electric current that is passedthrough the element may generate heat in the form of infrared radiationand function as an infrared emitter.

The temperature of the individual heaters 213-216 may be modulated bythe inhaled medicament delivery device 210 through the controller 211.The heaters 213-216 may uniformly heat the entire length of a conduitsuch as, for example, the aspiration tube 219. The heaters 213-216 maybe modulated so that they heat the aspiration tube 219 or the nozzle 212segmentally, meaning that only a certain segment or certain segments ofthe aspiration tube 219 or the nozzle 212 may be heated by theindividual heaters 213-216. For example, the aspiration tube 219 or thenozzle 212 may be heated over separate zones, each zone may, forexample, be heated to a different temperature, and the temperature ineach separate zone may be further modulated.

In an embodiment, temperature modulation control is achieved by asubject or healthcare provider via a user interface that is incommunication with a controller 211. A user interface may be, forexample, a digital user interface such as a touchscreen or, for example,a manual interface, or, for example, a combination of digital and manualelements. In an embodiment, a user interface may be directly attached tothe housing of the inhaled medicament delivery device 210. In anotherembodiment, a user interface wirelessly communicates with the controller211 on the inhaled medicament delivery device 210.

In another embodiment, temperature modulation is programmed into thecontroller 211 ahead of use by a subject 230. The temperature modulationprograming may comprise an algorithm for modulating a temperature, andmultiple algorithms comprising multiple temperature modulationvariations may be stored on the controller 211 on a microprocessormemory. In an embodiment, the controller 211 is configured to activatedifferent temperature modulations, and matches the optimal temperaturemodulation to the medicament being delivered via the inhaled medicamentdelivery device 210. For example, a particular temperature modulationmay be optimal for a particular medicament, and the optimal temperaturemodulation is activated by the controller 211 when the particularmedicament is used. When a different medicament having a differentoptimal temperature modulation associated with it is used, thecontroller 211 provides the proper temperature modulation that isassociated with that medicament.

Temperature modulation of the heat applied by heaters 213-216 may alsoprovide, for example, compensation for variability in environmentalconditions. For example, if the ambient temperature is cold or warm, thetemperature applied by the heaters 213-216 may be modulated tocompensate for or balance against the effect of the cold or warm ambienttemperature on the device and the inhalable medicament. Similarly,temperature modulation may, for example, compensate for a change inhumidity by, for example, increasing or decreasing the degree of vaporof the inhalable medicament as described herein. Similarly, temperaturemodulation may, for example, compensate for a pressure inducedtemperature reduction within the nozzle 212 during aerosol generation.

A liquid medicament is held within a cartridge 218 within a reservoir220. When either a reservoir tap or a penetrating nozzle 212 penetratesthe cartridge 218, a compressed propellant within the cartridge 218ejects the medicament from the reservoir 220 forming an aerosol. Wheneither a reservoir tap or a penetrating nozzle 212 penetrates thecartridge 218, a compressed propellant within the cartridge 218 ejectsthe medicament from the reservoir 220, forming an aerosol. The formedaerosol 221 travels through the penetrating nozzle 212 and then into theaspiration tube 219. While the aerosol 221 travels through theaspiration tube 219, the aerosol 221 is heated or otherwise thermallymodulated by heaters 213-216. When, the aerosol 221 is heated orotherwise thermally modulated by one or more of the heaters 213-216, oneor more droplets within the aerosol 221 change size so that the overallcomposition of the aerosol 221 changes as it is heated. As the aerosol221 travels along the aspiration tube 219, its composition changes inresponse to the application of heat or infrared radiation that isemitted by the heaters 213-216, and transforms into aerosol mixtures222, then 223, and then 224. It should be understood that the schematicof FIG. 2A is exemplary only, and the aerosol 221 need not necessarilychange in composition three times as it travels along the aspirationtube 219, and may in fact change in composition zero times or more as ittravels along the aspiration tube 219. Additionally, the composition ofthe aerosol 221 may change in a homogenous or heterogeneous fashion.

Mixtures 221-224 may comprise both vapor and aerosol. Different dropletsizes are illustrated by small circles and wavy lines in the aerosolcompositions shown in FIGS. 2A-2C. The vapor components in mixtures221-227 may be illustrated by wavy lines in FIGS. 2A-2C. The differingnumber of wavy lines and small circles shown in mixtures 221-227illustrate the varying amounts of vapor and aerosol present in therespective mixtures 221-227. The controller 211 controls heaters 213-216

After being thermally modulated in the aspiration tube 219 by theactivation of one or more of heaters 213-216 by the controller 211, amixture 225 is inhaled into the oropharynx 232 region by the subject230. While in the oropharynx 232, the mixture 225 may contact the tongue234 to provide the subject 230 with a taste sensation. In an embodiment,the medicament is mixed with a flavorant to provide, for example, asweet taste to a subject 230 when the medicament comes into contact withthe tongue 234 and oropharynx 232.

FIG. 2A shows the aerosol mixture 225 inhaled into the oropharynx 232region by the subject 230. While in the oropharynx 232 region, themixture 225 may contact the tongue 234 to provide the subject 230 with ataste sensation if the mixture 225 contains a flavorant. As the mixture225 travels through the lower airway region 233, the aerosol and/orvapor properties of the mixture 225 evolve. The mixture 225 then flowsto a distal airway region 231.

The evolution of the mixture 225 may be caused (at least in part) by atemperature change of the mixture 225. This temperature change may occuras a result of the mixture 225 with ambient air also being inhaled bythe subject 230. This temperature change may occur as a result ofinteraction with the body temperature of the subject 230. The evolutionmay be caused (at least in part) by the interaction of the aerosoldroplets with each other over time (e.g., collision of lesser sizeparticles causing the formation of larger particles or the agglomerationof particles).

The mixture 225 in the oropharynx 232 evolves into the mixture 226 inthe lower airway region 233. The mixture 226 is illustrated in the lowerairway region 233 as having an amount of vapor and an amount of aerosolwith a droplet size that is different from the mixture 225. The mixture226 should be understood to be the mixture 225 after evolution thattakes place while flowing from the oropharynx 232 and through the lowerairway region 233.

The mixture 226 in the lower airway region 233 evolves into a mixture227 in the distal airway region 231. The mixture 227 is illustrated inthe distal airway region 231 as having an amount of vapor and an amountof aerosol with a droplet size that is different from the mixture 226.The mixture 227 should be understood to be the mixture 226 afterevolution that takes place while flowing from the lower airway region233 to the distal airway region 231.

As the mixture 225 flows from the oropharynx 232 to a lung distal airwayregion 231, the aerosol and/or vapor properties of the mixture 225evolve. The mixture 225 flows to the lower airway region 233 and then toa more distal airway region 231 (shown by notional arrows in FIG. 2A).

The evolution of the mixture 225 may be caused (at least in part) by atemperature change of the mixture 225. This temperature change may occuras a result of the mixture 225 with ambient air also being inhaled bythe subject 230. This temperature change may occur as a result ofinteraction with the body temperature of the subject 230. The evolutionmay be caused (at least in part) by the interaction of the aerosoldroplets with each other over time (e.g., collision of lesser sizeparticles causing the formation of larger particles, or theagglomeration of particles).

The mixture 225 in the oropharynx 232 evolves into the mixture 226 inthe lower airway region 233. The mixture 226 is illustrated in the lowerairway region 233 as having an amount of vapor and an amount of aerosolwith a droplet size that is different from the mixture 225. The mixture226 should be understood to be the mixture 225 after evolution thattakes place while flowing from the oropharynx 232 and through the lowerairway region 233.

The mixture 226 in the lower airway region 233 evolves into the mixture227 in a distal airway region 231. The mixture 227 is illustrated in adistal airway region 231 as having an amount of vapor and an amount ofaerosol having a droplet size that is different from the mixture 226.The mixture 227 should be understood to be the mixture 226 afterevolution that takes place while flowing from the lower airway region233 to a distal airway region 231.

FIG. 2B is an illustration of air-mixture and thermal modulation. InFIG. 2B, an inhaled medicament delivery device 210 comprises a reservoir218, a medicament 220, a nozzle 212, a controller 211, heaters 213, 214,215, 216, and an aspiration tube 219. The reservoir 218 holds themedicament 220. The reservoir 218 is operatively coupled to the nozzle212 to provide the medicament 220 to the nozzle 212. The heaters 213-216are operatively coupled to the controller 211. The nozzle 212 injects anaerosol mixture 221 into the aspiration tube 219. The injection of theaerosol mixture 221, or the inhalation of the subject 230 draws air 229into the aspiration tube 219 to be mixed with the aerosol mixture 221.The injection of the aerosol mixture 221 may draw air 229 intoaspiration tube 219 using an air flow amplifier configuration. Such anair flow amplifier configuration may utilize the Coanda effect to directthe flow of air 229, and/or the aerosol mixture 221, and/or propellant(not shown in FIG. 2B) in order to amplify the flow of air 229 and themixtures 221-224 through the aspiration tube 219.

The aerosol mixture 221 is heated, or otherwise thermally modulated, byone or more of the heaters 213-216 to produce the mixtures 222-224. Themixtures 221-224 are comprised of vapor and aerosol. The vaporcomponents in the mixtures 221-227 are illustrated by wavy lines inFIGS. 2A-2C. The aerosol components in the mixtures 221-227 areillustrated as small circles in FIGS. 2A-2C. The differing number ofwavy lines and small circles shown in mixtures 221-227 illustrate thevarying amounts of vapor and aerosol present in the respective mixtures221-227. The controller 211 controls the heaters 213-216.

The inhaled medicament delivery device 210 may generate a partial orcomplete vapor from the aerosolized medicament 220. A partial vapor may,for example, be mixed with an aerosol. The particle size of themedicament 220 is smaller in the vapor than in the aerosol. Thevariation in the particle size of the medicament 220 can be controlledby, for example, controlling the degree of vaporization. For example, acomplete vapor will deliver a smaller particle size medicament 220 thanthe medicament 220 particle delivered by an aerosol.

The degree of vaporization of the aerosolized medicament 220 increaseswith an increase in the amount of heat applied. Thus, the hotter theaerosolized medicament 220 becomes, the greater the quantity and speedof vapor generation inside the inhaled medicament delivery device 210.

Variations of the inhaled medicament delivery device 210 with respect topartial and complete vapor generation from the aerosolized medicament220 are described herein.

FIG. 2B shows a schematic view of the actions of the heaters 213-216.Activated heaters 213-216, that are actively emitting heat, areillustrated in FIG. 2B by one or more small ‘thermal radiation’ (i.e.,‘z’ shaped) arrows in proximity to a respective heater 213-216. Theselective presence or absence of such arrows in the schematicrepresentation of the heaters 213-216 is meant to illustratecontrollable thermal modulation of heating along the aspiration tube219. That is, as shown, the controller 211 may, for example, cause theheaters 213, 214, and 216, to emit heat along the aspiration tube 219,while the heater 215 is not activated by the controller 211. It shouldbe understood that through the controller 211, the heaters 213-216 maybe sequentially controlled in any number of ways including but notlimited to control over individual heater activation, control overindividual heater activation timing, and control over individual heateractivation duration.

The mixture 222 is illustrated in FIG. 2B as having, for example, morevapor and a smaller droplet size relative to the mixture 221. Themixture 222 is thermally modulated into the mixture 223. The mixture 223is illustrated in FIG. 2B as having, for example, more vapor and asmaller droplet size relative to the mixture 222. The mixture 223 isthermally modulated into the mixture 224. The mixture 224 is illustratedin FIG. 2B as having, for example, more vapor and a smaller droplet sizerelative to the mixture 223. Mixture 224 is inhaled by the subject 230.It should be understood that any of the mixtures 221-224 may comprisevapor mixed with aerosol or a mixture of different sized aerosol drops.

Thermal modulation may also be used in order to convey a warm aerosol orvapor to the subject 230 to replicate a sensory cue or sensation ofinhaling smoke. Furthermore, a warm aerosol or vapor that is of the sameor similar to the physiologic temperature of the airway may be used inorder to convey a more pleasant aerosol or vapor for inhalation,reducing patient resistance to inhalation of the aerosol andconcurrently improving the delivery of the medicament 220.

FIG. 2C is an illustration of preheated air-mixture and thermalmodulation. In FIG. 2C, an inhaled medicament delivery device 210comprises a reservoir 218, a medicament 220, a nozzle 212, a heater 214,and an aspiration tube 219. The reservoir 218 holds the medicament 220.The reservoir 220 is operatively coupled to the nozzle 212 to providethe medicament 220 to the nozzle 212. The heaters 213-216 areoperatively coupled to the controller 211. The nozzle 212 injects anaerosol mixture 221 into the aspiration tube 219. The injection of theaerosol mixture 221, or the inhalation of the subject 230, draws air 229along a passageway 228 and then into the aspiration tube 219 to be mixedwith the aerosol mixture 221. As the air 229 is drawn along thepassageway 228, the air 229 is heated. The air 229 may be heated by aheater 214 or other heaters (not shown in FIG. 2C). The air 229 may beheated by contact or proximity to the aspiration tube 219, which isheated by at least the heater 214. The passageway 228 may be configuredsuch that the air 229 does not contact the heater 214 elements. Forexample, the passageway 228 may be configured on the outside surface ofthe aspiration tube 219 such that the aspiration tube 219 (or anotherbarrier) separates the heater 214 from the air 229.

FIG. 3A shows a medicament cartridge 340 and a reservoir tap 312 as theyare positioned relative to one another in an embodiment of an inhaledmedicament delivery device 310. More specifically, FIG. 3A shows themedicament cartridge 340 and the reservoir tap 312 positioned at thedistal end of the inhaled medicament delivery device 310 (only distalend of the inhaled medicament delivery device 310 is shown). Themedicament cartridge 340 is coupled to a housing that contains thereservoir tap 312 within it. The reservoir tap 312 is configured toslideably move along a length of the inside of the housing.

The medicament cartridge 340 comprises a porous reservoir material 342,a medicament 320, and a cartridge seal 343. The reservoir tap 312comprises a tap shaft 353 and a nozzle 352. The tap shaft 353 has ahollow interior and includes ports 355 that allow liquids or gasses toflow from outside the reservoir tap 312 into the tap shaft 353. Thehollow interior of the tap shaft 353 is continuous with the nozzle 352so that liquids or gasses passed into the interior of the tap shaft 355flow freely into the nozzle 352. The medicament cartridge 340 may beseparable and re-attachable from the inhaled medicament delivery device310.

In an embodiment, the inhaled medicament delivery device 310 comprisestwo or more couplable hollow bodies. In the shown embodiment, inhaledmedicament delivery device 310 comprises two hollow bodies that arecoupled so that the interior of the first body is separated from theinterior of the second body. The interiors of the two coupled bodies ofthe inhaled medicament delivery device 310 may be separated by apenetrable seal 343. In an embodiment, the inhaled medicament deliverydevice 310 comprises a medicament cartridge 340 that contains aninhalable medicament and the body that the medicament cartridge 340couples with comprises a hollow housing containing the reservoir tap312.

In an embodiment, the two hollow bodies are reversibly coupled via acoupling mechanism. A coupling mechanism may comprise a screw-in systemwherein both bodies have interlocking threaded sections that screwtogether to secure the two bodies together. A coupling mechanism maycomprise a clip-in mechanism where one or more male appendage on a firsthollow body lock into one or more female appendages on a second hollowbody, so that the male and female appendages lock together. It should beunderstood that other coupling mechanisms for interlocking two hollowbodies that couple together are suitable for use with the devices andmethods described herein and the examples above is not to be understoodas limiting in any way.

In an embodiment, a reversibly coupled medicament cartridge 340 may bedisconnected from the inhaled medicament delivery device 310. Forexample, after the medicament 320 is dispensed to a subject, an expendedcartridge may be disconnected from the inhaled medicament deliverydevice 310. A plurality of the medicament cartridges 340 may beinterchanged using the coupling mechanism to couple and then de-couplethe medicament cartridges 340 of the plurality of medicament cartridges340. A plurality of the medicament cartridges 340 that may beinterchangeably coupled with the inhaled medicament delivery device 310may contain the same medicament 320. The medicament cartridges 340 thatmay be interchangeably coupled with the inhaled medicament deliverydevice 310 may contain different medicaments 320. In an embodiment, theinhaled medicament delivery device 310 self-sterilizes between theexchange of two different reversibly couplable medicament cartridges 340in order to, for example, prevent cross-contamination of differentmedicaments 320 or different cartridge loads. Self-sterilization of theinhaled medicament delivery device 310 may occur through activation ofone or more heaters to a temperature adequate to sterilize the inhaledmedicament delivery device 310. Alternatively or additionally,components that contact the medicament 320 may be exchanged when themedicament cartridge 340 is exchanged for a new cartridge, such as, forexample, exchanging the aspiration tube (not shown) or the mouthpiece orthe reservoir tap 312 along with exchanging the medicament cartridge340. In an embodiment, the medicament cartridge 340 may be replaced withone or more cartridges adapted to clean and sterilize the inhaledmedicament delivery device 310. Such a cartridge or cartridges may flushcomponents that contact the medicament with water, solvents, sterilizingagents, drying agents, and/or lubricants to restore optimal deviceoperation and/or prevent cross-contamination, etc.

In an embodiment, the inhaled medicament delivery device 310 comprises amedicament cartridge 340 that is continuous with a housing that containsthe reservoir tap 312. That is, the medicament cartridge 340 and thehousing are formed as a single unit rather than two components that arecoupled together with a mechanical coupling mechanism. In thisembodiment, the medicament cartridge 340 is not configured to bedecoupled from the inhaled medicament delivery device 310.

In an embodiment, a medicament cartridge 340 is configured to bereversibly coupled with a housing of an inhaled medicament deliverydevice 310 and is disposable.

In an embodiment, a medicament cartridge 340 is refillable and reusable.

In an embodiment, the entire inhaled medicament delivery device 310,including the medicament cartridge 340 along with the housing, isdisposable.

In an embodiment, a reservoir tap 312 comprises a hollow body with apenetrating tip. The penetrating tip may be, for example, sharp, or, forexample, blunt. The reservoir tap 312 may be advanced towards the seal343 or withdrawn away from the seal 343 within the inhaled medicamentdelivery device 310 housing. For example, movement of the reservoir tap312 may occur on an axis that is parallel to the long axis of theinhaled medicament delivery device 310 housing or a conduit within thehousing that contains the reservoir tap 312.

In an embodiment, a first hollow body of the inhaled medicament deliverydevice 310, comprising the cartridge 340, couples with a second hollowbody of the inhaled medicament delivery device 310 that contains thereservoir tap 312 within it, so that the penetrating tip of thereservoir tap 312 faces the surface of the penetrable seal 343.

In an embodiment, the reservoir tap 312 includes one or more ports 355.In an embodiment, the reservoir tap 312 is configured to be advanced sothat the penetrating body of the reservoir tap 312 penetrates apenetrable seal 343. The reservoir tap 312 is advanced so that when theseal 343 is penetrated, one or more ports 355 is positioned eitherwithin the medicament cartridge 340 or positioned within the penetratedseal 343, so that the port 355 within the seal 343 is covered by theseal 343. In the inactivated position, the seal 343 is not penetrated aby tap shaft 353 (or at least not penetrated or configured such thatmedicament 320 is allowed to flow into reservoir tap 312).

In an embodiment, the ports 355 are covered while the reservoir tap 312is entirely within the housing and are uncovered once the reservoir tap312 penetrates the seal 343. For example, in an embodiment, thereservoir tap 312 comprises two rotating portions each with ports 355that are configured to align, and wherein one rotating portion is withinthe other. When both rotating portions of the reservoir tap 312 rotateto align the ports, the ports 355 are open. When both rotating portionsof the reservoir tap 312 are rotated so that their respective ports 355are not aligned, the ports 355 are covered. In another example, in anembodiment, the ports 355 are covered by a slideably removable coverthat is pulled back when or after the reservoir tap 312 penetrates theseal 343.

In an embodiment, the medicament cartridge 340 contains a porousreservoir 342, which contains a medicament 320, and a propellant gas341. In the embodiment shown, the porous reservoir 342 comprises ahydrophobic material, such as, for example, a hydrophobic polymercomprising of pores or channels, or for example a hydrophobic porousceramic. The medicament 320 in liquid form is retained by hydrophobicforces within the pores of the porous reservoir material 342. The entiremedicament cartridge 340 is pressurized so that the propellant gas 341is compressed and is substantially prevented from passing through thepores or channels of the porous reservoir material 342 while themedicament cartridge 340 is pressurized. In an embodiment, themedicament cartridge 340 is enclosed on all but one side by a housing,and the opening in the medicament cartridge 340 is sealed by thepenetrable seal 343. The term “cartridge” may refer to the entire distalassembly which includes the medicament cartridge 340, the liquidreservoir, and other components. The term “cartridge” may refer to thepart of the inhaled medicament delivery device 310 or cartridge thatcontains the pressurized gas or just the medicament 320. The medicamentcartridge 340 is sealed by a valve assembly and or a septum.

In an embodiment, the porous reservoir material 342 comprises a porousor matrix material that is hydrophobic and is configured to retain aliquid medicament formulation through capillary action or similar meansin void spaces in the matrix or pores in the porous reservoir material342. Materials such as ceramics, glasses, polymers, or plastics may besuitable for use as the porous reservoir material 342. Non-limitingexamples of hydrophobic polymer materials include Acrylics, Amides,Carbonates, Dienes, Esters, Ethers, Fluorocarbons, Olefins, Styrenes,Vinyl Acetals, Vinyl Esters, and Vinylpyridine. The porous reservoirmaterial 342 may comprise, for example, a matrix or honeycomb structure.In an embodiment, the porous reservoir material 342 is positionedbetween the propellant gas 341 and the penetrable seal 343. Thepropellant gas 341 may pass into the pores of the porous reservoirmaterial 342, while the hydrophobic property of the porous reservoirmaterial 342 holds or traps the fluid within the pores of the porousreservoir material 342. The fluid held within the pores of the porousreservoir material 342 is analogous to water held within a sponge. Whenthe pressure in the medicament cartridge 340 equilibrates with ambientpressure because, for example, the seal 343 was penetrated, thepropellant gas 341 forcefully expands into the pores of the porousreservoir material 342. The forceful expansion of the propellant gas 341ejects the fluid medicament 320 out of the pores of the porous reservoirmaterial 342.

In an embodiment, the porous reservoir material 342 allows for theinhaled medicament delivery device 310 to be operated regardless oforientation. The orientation-independent operation of the inhaledmedicament delivery device 310 is achieved because the liquidformulation of the medicament 320 is always maintained in the sameposition relative to the compressed propellant gas 341. That is, themedicament 320 is always maintained in a proximal position to the portor ports 355 when the reservoir tap 312 penetrates the penetrable seal343, and the compressed propellant gas 341 is always positioned distalto the reservoir tap 312 relative to the positon of the medicament 320.Said yet another way, the propellant gas 341 is always behind themedicament 320, relative to the reservoir tap 312, regardless of how thesubject positions the inhaled medicament delivery device 310 relative totheir mouth. Because the fluid is held in place by, for example, theporous reservoir material 342, a subject can use the inhaled medicamentdelivery device 310 while, for example, lying on their back with themedicament cartridge 340, for example, towards the ceiling. Because thedevice may be used by a subject in the prone or sitting positons, theorientation-independence of the inhaled medicament delivery device 310is advantageous to, for example, provide an inhalable medicament 320 toa bedbound patient with poor mobility. It should be understood thatthere are other variations that can facilitate the holding of the fluidwithin the medicament cartridge 340 in a fixed position within themedicament cartridge 340, and the examples and embodiments describedherein should not be understood to be limiting in any way.

In an embodiment, the penetrable seal 343 comprises rubber. In anembodiment, the penetrable seal 343 comprises a plastic. In anembodiment, the seal 343 comprises a polymer. It should be understoodthat other materials are suitable for construction of a penetrable seal343 and the examples above should not be taken to be limiting. In anembodiment, the penetrable seal 343 is self-sealing, so that after beingpunctured the puncture in the penetrable seal 343 closes by itself dueto, for example, the elastic properties of the seal 343 material. Theseal 343 functions to create an airtight seal 343 of the medicamentcartridge 340 to maintain the pressurization within the medicamentcartridge 340. When the seal 343 is punctured by the reservoir tap 312,the pressure within the medicament cartridge 343 equilibrates withambient pressure. Non-limiting examples of suitable seal 343 materialsinclude Silicone Rubber, Polyacrylate Rubber, Ethylene-acrylate Rubber,Polyester Urethane, Bromo Isobutylene Isoprene, Chloro IsobutyleneIsoprene, Chlorosulphonated Polyethylene, Polyether Urethane, FluoroSilicone, and Vinyl Methyl Silicone. The seal 343 material may, in anembodiment, contain a metal imbedded in the material such as silver orcopper to prevent the growth of microorganisms on the seal or anothersuitable antimicrobial agent imbedded into the seal 343 material. In anembodiment, the seal 343 is comprised of a self-healing material. Theseal 343 allows for the tap shaft 353 to slide along the proximal todistal direction (and back). In an embodiment, the second body thatcontains the reservoir tap 312 is also sealed with a penetrable seal343.

In an embodiment, the medicament cartridge 340 may contain a propellantgas 341 such as carbon dioxide (CO₂). The propellant gas 341 may becompressed within the medicament cartridge 340 when, for example, themedicament cartridge 340 is pressurized. A decrease in pressure insideof the medicament cartridge 340 will, for example, result in anexpansion of the propellant gas 341 into the pores of the porousreservoir material 342.

The propellant gas 341 is held in the medicament cartridge 340 underpressure such as to provide a positive pressure that can drive themedicament 320 in the medicament cartridge 340 out of the medicamentcartridge 340 and through the nozzle 352 to generate an aerosol.Interior to the medicament cartridge 340 is the porous reservoirmaterial 342 that occupies a proximal area of the medicament cartridge340. The porous reservoir material 342 serves to hold, retain, orotherwise trap the liquid formulation of the medicament 320. The porousreservoir material 342 serves to hold the medicament 320 such a mannerthat when the inhaled medicament delivery device 310 is activated, thepropellant gas 341 will be forced through the porous reservoir material342 and as a result, displace the liquid medicament 320 out of theporous reservoir material 342 for delivery to the tap shaft 353 and thento the nozzle 352. The medicament cartridge 340 comprises propellant gas341, and is the portion that is typically located most distally alongthe inhaled medicament delivery device 310 from the mouthpiece. Theporous reservoir material 342 may be positioned adjacent to themedicament cartridge 340, and the pores of the porous reservoir material342 may communicate with the interior of the medicament cartridge 340 sothat, for example, a propellant gas 341 may pass from the medicamentcartridge 340 and into the pores of the porous reservoir material 342.

In an embodiment, the porous reservoir material 342 may be omitted wherethe liquid formulation of the medicament 320 is brought into a misciblesolution with the propellant gas 341.

When the inhaled medicament delivery device 310 is not activated, theports 355 on the tap shaft 353 can be occluded or otherwise blocked bythe seal 343. When the reservoir tap 312 is activated to move in thedistal direction far enough that the reservoir tap 312 penetrates thepenetrable seal 343, and the ports 355 exit the seal 343 and enter themedicament cartridge 340, the liquid formulation of the medicament 320enters the ports 355, travels through the tap shaft 353, and exits thenozzle 352.

The movement of the reservoir tap 312 may be driven and controlled in anumber of ways, including the following non-limiting examples. Themovement of the reservoir tap 312 may be, for example, spring driven.The movement of the reservoir tap 312 may be, for example, driven byelectromagnetic forces. The movement of the reservoir tap 312 may be,for example, driven by pressurized air or gas. The movement of thereservoir tap 312 may be, for example, driven by an electromechanicalactuator or servo.

FIG. 3B is an illustration of the functioning of a reservoir tap 312 ofan inhaled medicament delivery device 310. In FIG. 3B, the reservoir tap312 is positioned such that a tap shaft 353 penetrates a seal 343 to anextent that leaves ports 355 exposed to the interior of a medicamentcartridge 340. The ports 355 are exposed to the interior of themedicament cartridge 340 so that a medicament 320 may enter a hollowinterior cavity of the tap shaft 353 and flow from the medicamentcartridge 340 to a nozzle 352 under the force of a propellant gas 341.

As illustrated in FIG. 3B, when the reservoir tap 312 is in an activatedposition, the propellant gas 341 enters a porous reservoir material 342to displace a medicament 320 (shown in FIG. 3B by arrows 391).

As shown by arrows 392, as the medicament 320 is displaced from theporous reservoir material 342, the medicament 320 travels to the ports355. As shown by arrows 393, the medicament 320 enters the ports 355 andtravels down the tap shaft 353 to exit the nozzle 352 as an aerosolmixture 321.

The pressure within the reservoir tap 312 may be lower than the pressurewithin the medicament cartridge 340. When the reservoir tap 312penetrates and passes through the seal 343, the pressure inside themedicament cartridge 340 drops to equilibrate with the lower pressurewithin the reservoir tap 312. In an embodiment, the pressurized gasprovides the propellant force to drive the liquid medicament 320 out ofthe medicament cartridge 340 and into the nozzle 352.

The speed and force with which the propellant gas 341 expands may bedetermined by factors such as, for example, the pressure differentialbetween the reservoir tap 312 and the medicament cartridge 340 as wellas the speed at which the pressure inside the medicament cartridge 340is dropped. When the reservoir tap 312 penetrates the seal 343, thepropellant gas 341 expands out of the medicament cartridge 340 anddisplaces the liquid medicament 320 in the cartridge 340. When thepropellant gas 341 powerfully expands out of the medicament cartridge340, the propellant gas 341 may eject the medicament 320 liquid out ofthe medicament cartridge 340 and into the tap shaft 353 through thereservoir tap 312.

The ejected medicament 320 liquid may disperse into smaller droplets ofliquid within the reservoir tap 312, thus forming an aerosol. The formedaerosol may be propelled by the force of the propellant gas 341 throughthe length of the reservoir tap 312, through the tap shaft 353, throughthe mouth of a subject, through the oropharynx of a subject, and intothe lungs of a subject.

In another embodiment, features are added that act as air flowamplifiers that increase the velocity of the medicament 320 and/orvolume of air as it travels through the mechanisms and devices describedherein. For example, in an embodiment, the Venturi effect is utilized toincrease the velocity of the medicament 320 liquid within the inhaledmedicament delivery device 310. The Venturi effect describes an increasein the velocity of a fluid traveling through a constriction in aconduit. A constriction in at least a segment of the reservoir tap 312,or the nozzle 352, may create an area of increased fluid velocitythrough that constricted segment. For example, the ports 355 maycomprise narrow channels for the passage of liquid medicament 320 intothe reservoir tap 312. The travel of the medicament 320 liquid from themedicament cartridge 340 is accelerated as it passes through narrowchannels of the ports 355 into the reservoir tap 312. The greater thevelocity of the fluid as it travels into and through the reservoir tap312, typically the greater the degree of aerosol formation. Also, whenthe medicament 320 liquid travels with greater velocity through thereservoir tap 312, the inhaled medicament delivery device 310 maydeliver a larger volume in a shorter time. For example, in anembodiment, the reservoir tap 312 or the nozzle 352 may comprise astructure that generates a Coanda effect further increasing the velocityof the fluid traveling through the reservoir tap 312 from the medicamentcartridge 340.

In another embodiment, the phase change of a liquid excipient to a gas,such as, for example, glycerol, may occur causing an increase inpropulsion and thus an increase in the velocity of the medicament 320liquid traveling through the reservoir tap 312 and the tap shaft 353.

Generally, the embodiments comprising the Venturi effect, the Coandaeffect, or a phase change in a liquid excipient to a gas can promoteairflow magnification within the inhaled medicament delivery device 310.A benefit of airflow magnification within the inhaled medicamentdelivery device 310 is that it may provide increased per use volume ofthe delivered inhalable medicament 320 independent of the size andvolume of the medicament cartridge 340. The Coanda effect may beutilized to orient a circumferential (in relation to the jet ports inthe nozzle) air envelope. The cylindrical air envelope can serve tofocus the aerosol generated by the jet ports (or ultrasonic nozzle) toreduce or mitigate impact of the aerosol onto the interior surface ofthe aspiration tube and thus reduce the amount of drug loss in theinhaled medicament delivery device 310 or serving to reduce or mitigatethe aerosol being exposed to a higher temperature on the surface of thetap shaft 353.

In an embodiment, a nozzle 352 comprises an ultrasonic nozzle 352. Theultrasonic nozzle 352 is connected to a power source and at least onepiezoelectric transducer that creates ultrasonic sound waves within theultrasonic nozzle 352. When a fluid is in contact with an ultrasonicsound wave within an ultrasonic nozzle 352, a capillary wave is formedwithin the fluid. When the amplitude of the capillary wave reaches acertain height, the fluid separates into droplets creating an aerosolwithin the ultrasonic nozzle 352.

The pressurized fluid within the medicament cartridge 340 may comprise amedicament 320 that is delivered in an inhalable form to a subject usingthe inhaled medicament delivery device 310.

The aerosol mixture 321 may be further thermally modulated and/or mixedwith additional air by the inhaled medicament delivery device 310. Theaerosol mixture 321 may correspond to, or be a precursor to, the mixture121 and/or the mixture 221, described herein.

FIG. 3C is an illustration of a tamper-resistant medicament cartridgeand a reservoir tap 312 for an inhaled medicament delivery device 310.In FIG. 3C, the inhaled medicament delivery device 310 comprises thetamper-resistant cartridge 349, and the reservoir tap 312. Thetamper-resistant cartridge 349 includes a porous reservoir material 342,a medicament 320, a cartridge seal 343, a neutralizing agent 345, and anencapsulation 346. The reservoir tap 312 includes a tap shaft 353 and anozzle 352. The encapsulation 346 separates a neutralizing agent 345from the medicament 320. The encapsulation 346 encases the neutralizingagent 345 such that, if the encapsulation 346 is penetrated, theneutralizing agent 345 will be allowed to react with the medicament 320,thereby rendering the liquid formulation of the medicament 320inaccessible or functionally neutralized. The tamper-resistant cartridge349 may be separable from and re-attachable to the inhaled medicamentdelivery device 310 without penetrating the encapsulation 346 orotherwise releasing the neutralizing agent 345 to react with themedicament 320. The reservoir tap 312 is configured to penetrate thetamper-resistant cartridge 349 without penetrating the encapsulation 346or otherwise releasing the neutralizing agent 345 to react with themedicament 320.

FIG. 3D is an illustration of the neutralization of a medicament 320 bya tamper-resistant cartridge 349. In FIG. 3D, a penetrating object 392enters the interior of the tamper-resistant cartridge 349. In order toenter the interior of the tamper-resistant cartridge 349, thepenetrating object 392 ruptures or otherwise destroys the integrity ofthe encapsulation 346. With the integrity of the encapsulation 346compromised, the neutralizing agent 345 can contact and thereby reactwith the medicament 320, thereby rendering the liquid formulation of themedicament 320 inaccessible or functionally neutralized. The porousreservoir material 342 may contain encapsulated absorbents orneutralizing agents (not illustrated) such as to prevent intentional orunintentional access or contact with the liquid formulation of themedicament 320. The encapsulated absorbent, such as charcoal, would beencased in a hydrophobic casing such as a plastic, polymer, ceramic, orglass such that if the medicament cartridge 340 was accessed and theporous reservoir material 342 was removed (or penetrated in a manner notcorresponding to the activation of the reservoir tap 312), theencapsulation 346 would rupture or otherwise allow the absorbent orneutralizing agent 345 to come into contact with the liquid formulationof the medicament 320 and render the medicament 320 inaccessible orfunctionally neutralized.

FIG. 4A is an illustration the operation of a medicament cartridge withmedicament bladder embodiment. In FIG. 4A, an inhaled medicamentdelivery device 410 comprises a cartridge 440, and a reservoir tap 412.The cartridge 440 includes a bladder 444, a medicament 420, and acartridge seal 443. The reservoir tap 412 includes a tap shaft 453, anda nozzle 452. The tap shaft 453 is hollow and includes ports 455 thatallow liquids or gasses to flow from outside the reservoir tap 412, intothe tap shaft 453, and out the nozzle 452. The bladder 444 holds themedicament 420. The cartridge 440 may be separable and re-attachablefrom the inhaled medicament delivery device 410. The compressiblebladder 444 is preferably positioned proximally to the pressurizedgaseous propellant relative to the reservoir tap 412. When the pressurechanges within the cartridge 440, the gaseous propellant expands,compressing the liquid containing compressible bladder 444. The forcefulcompression of the bladder 444 causes an ejection of the medicament 420liquid within it. It should be understood that the compressible bladder444 can have alternate variations such as, for example, a compressiblebag or balloon. In an embodiment, the bladder 444 may be distensible andexert a pressure on the liquid wholly or partially (in conjunction withthe pressurized gas) drive the liquid into the nozzle. Also, the bladder444 may be comprised of a plurality of layers, such that between theinner bladder 444, which contains the liquid medicament 420, and theouter bladder 444 there is a space that could contain dry neutralizingagent or absorbent material to render the active excipient inactive orto otherwise absorb and capture the active excipient. A liquidneutralizing agent could also be contained in the space between theouter surface of the inner bladder 444 and the inner surface of theouter bladder 444.

The bladder 444 allows for the inhaled medicament delivery device 410 tobe activated in a fashion that is independent of the orientation inspace of the inhaled medicament delivery device 410. In an embodiment,the bladder 444 is positioned in the cartridge directly adjacent to thecartridge seal 443. In an embodiment, the bladder 444 shares a commonwall with the cartridge seal 443. In an embodiment, this position placesthe bladder 444 along with the liquid medicament 420 inside of it in aposition that is more proximal to a subject than a propellant gas. Saidanother way, in this embodiment, no matter what the orientation of thedevice, the medicament 420 within the bladder 444 is always positionedbetween most of the propellant 441 in the cartridge 440 and thecartridge seal 443. In this way, when the cartridge seal 443 ispenetrated, the propellant 441 be will behind the liquid medicament 420and eject the medicament 420 into the reservoir tap 412 independently ofthe orientation in which the inhalable medicament delivery device 410 isheld.

In FIG. 4A, the reservoir tap 412 is illustrated, positioned such thattap shaft 412 penetrates the cartridge seal 443 to an extent that leavesthe ports 455 exposed to the interior of the bladder 444. The ports 455are exposed to the interior of the bladder 444 so that the medicament420 may enter a hollow interior cavity of the tap shaft 453 and flowfrom the cartridge 440 to the nozzle 452 under the force that thepropellant 441 exerts on the bladder 444.

As also illustrated in FIG. 4A, when the reservoir tap 412 is in anactivated position, the propellant 441 exerts a force (illustrated byarrows 491) on the bladder 444 to push the medicament 420 out of thereservoir 342 via the ports 455. The medicament 420 enters the ports 455and travels down the tap shaft 453 to exit the nozzle 452 as the aerosolmixture 421. The aerosol mixture 421 may be further thermally modulatedand/or mixed with additional air by the inhaled medicament deliverydevice 410. The aerosol mixture 421 may correspond to, or be a precursorto, the mixture 121 and/or the mixture 221, described herein.

In an embodiment, the liquid medicament 420 may be in a distensiblebladder 444. In an embodiment, the liquid medicament 420 with thebladder 444 distends the bladder 444 like an overfilled balloon togenerate an intrinsic pressure within the walls of the bladder 444. Thepressure caused by the distended bladder 444 may provide a force(retains the liquid under a pressure) that may propel the liquid out ofthe liquid reservoir and into the nozzle 452 when the cartridge seal 443and cartridge 440 are penetrated. This pressure may be a result of anelastic force (e.g., like a stretched rubber band) provided by thedistended bladder 444.

FIG. 4B is an illustration the operation of a tamper-resistantmedicament cartridge. In FIG. 4B, the inhaled medicamenttamper-resistant cartridge 449 includes a bladder 444, a medicament 420,a cartridge seal 443, a neutralizing agent 445, and a bladder 446. Thebladder 444 holds the medicament 420. The bladder 446 holds theneutralizing agent 445. The bladder 446 holds neutralizing agent 445 ina space between an outer wall of the bladder 444 and an inner wall ofthe bladder 446. Thus, in order to penetrate the bladder 444 fromoutside of the inhaled medicament tamper-resistant cartridge 449 (exceptthrough the seal 443), the penetrating object would need to firstpenetrate the bladder 446.

The bladder 444 separates the neutralizing agent 445 held by the bladder446 from the medicament 420. The bladder 346 holds the neutralizingagent 445 around the outer wall of the bladder 444, such that if thebladder 444 is penetrated, the neutralizing agent 445 will be allowed toreact with the medicament 420, thereby rendering the liquid formulationof the medicament 420 inaccessible or functionally neutralized. Theinhaled medicament tamper-resistant cartridge 449 may be separable andre-attachable from an inhaled medicament delivery device 410 withoutpenetrating the bladders 446,444, or otherwise releasing theneutralizing agent 445 to react with the medicament 420.

In an embodiment, a cartridge comprises a pressure plate positionedbetween the medicament and the distal most portion of the cartridge. Inan embodiment, a pressure plate is a plate or sliding seal (e.g., likethe plunger seal of a syringe) having the same dimensions as theinterior of the cartridge. In an embodiment, a pressure plate has aproximal side or surface facing the proximal portion or section of acartridge, and a distal side or surface facing the distal portion orsection of a cartridge. In an embodiment, the pressure plate effectivelyforms a seal with the cartridge walls so that a medicament within thecartridge is positioned entirely on a proximal side of the pressureplate. In an embodiment, the pressure plate is slideably moveable alongthe interior of the cartridge. For example, the pressure plate may beconfigured to move along a track within the cartridge interior. In anembodiment, a change in pressure within the cartridge causes a pressureplate to move forward towards the proximal end of a cartridge. When apressure plate moves forward within the cartridge towards the proximalportion of the cartridge, the medicament on the proximal side of thepressure plate is pushed or ejected out of the cartridge by the pressureplate. In an embodiment, the portion of the cartridge that is on theproximal side of the pressure plate is pressurized so that a pressureplate is pushed towards the distal section of the cartridge. When thepressure on the proximal side of the pressure plate drops, the pressureplate will be caused to move forward within the cartridge, ejecting amedicament positioned on a proximal side of the pressure plate. In anembodiment, a compressed gaseous propellant is positioned on the distalside of a pressure plate. When a pressure is dropped within a cartridgethe gaseous propellant positioned on the distal side of the pressureplate expands, moving the pressure plate forward towards the proximalend of the cartridge, and pushing or ejecting the medicament positionedon the proximal side of the pressure plate out of the cartridge. In anembodiment, the movement of the pressure plate within the cartridge iselectronically conveyed such that the volume of the medicament or numberof remaining doses is correspondingly determined based on the relativeposition of the pressure plate. In an embodiment, the relative positionof the pressure plate is communicated electronically with the device,such that of there is movement of the pressure plate that does notcorrespond to an intentional activation as would be the case oftampering, damage, or malfunction, which could render the deviceinactive.

In an embodiment, the pressure plate may be moved by mechanical (e.g.,lead screw) or electrical means to provide doses. In this manner, thedistance traveled by the pressure plate may be monitored to determinethe remaining volume of the medicament or number of remaining doses.Likewise, the distance traveled by the pressure plate may be monitoredto determine the volume of each dose and/or the volume and/or number ofdoses already expended. The number of turns a lead screw is advanced canprovide a highly accurate way to measure and/or provide doses of themedicament.

FIG. 5A is an illustration of a reservoir and reservoir tap positionedto provide a first medicament dosing/mixture. In FIG. 5A, an inhaledmedicament delivery device 510 comprises a cartridge 540 and a reservoirtap 512. The cartridge 540 includes a medicament 520, and a cartridgeseal 543. The reservoir tap 512 includes a tap shaft 553 and a nozzle552. The tap shaft 553 is hollow and includes first ports 555 and secondports 556 that allow liquids or gasses to flow from outside thereservoir tap 512, into the tap shaft 553, and out the nozzle 552. Thecartridge 540 may be separable and re-attachable from the inhaledmedicament delivery device 510.

In FIG. 5A, the reservoir tap 512 is illustrated positioned such thatthe tap shaft 512 penetrates the seal 543 to an extent that leaves boththe first ports 555 and the second ports 556 exposed to receive themedicament 520. As shown by arrows 593, the first ports 555 and thesecond ports 556 are both exposed to such that the medicament 520 mayenter a hollow interior cavity of the tap shaft 553 and flow from thecartridge 540 to the nozzle 553 under the force of a propellant. Sincethe first ports 555 and the second ports 556 both allow the medicament520 to enter the hollow interior cavity of the tap shaft 553, a greaterflow of the medicament 520 is expected than if just one of the first orsecond ports 555, 556 were to allow the medicament 520 to enter thehollow interior cavity of the tap shaft 553.

As illustrated in FIG. 5A, when the reservoir tap 512 is in a firstactivated position, the medicament 520 enters the first ports 555 andthe second ports 556 and travels down the tap shaft 553 to exit thenozzle 552 as an aerosol mixture 521. The aerosol mixture 521 may befurther thermally modulated and/or mixed with additional air by theinhaled medicament delivery device 510. The aerosol mixture 521 maycorrespond to, or be a precursor to, the mixture 121 and/or the mixture221, described herein.

As illustrated in FIG. 5B, when the reservoir tap 512 is in a secondactivated position, the medicament 520 enters only the first ports 555and not the second ports 556. The second ports 556 are not exposed tothe medicament 520. The second ports 556 may be prevented from beingexposed to the medicament 520 because the second ports 556 are occludedby the seal 543. The second ports 556 may be prevented from beingexposed to the medicament 520 because, when the reservoir tap 512 is inthe second activated position, the ports 556 are still outside of thecartridge 540 or otherwise positioned in order to prevent the flow ofthe medicament 520 via the second ports 556.

As shown by arrow 594, the medicament 520 enters only the first ports555 and travels down the tap shaft 553 to exit the nozzle 552 as anaerosol mixture 522. The aerosol mixture 522 may be further thermallymodulated and/or mixed with additional air by the inhaled medicamentdelivery device 510. The aerosol mixture 522 may correspond to, or be aprecursor to, the mixture 121 and/or the mixture 221, described herein.

FIG. 5C is an illustration of a cartridge configured to control amedicament dosing/mixture. In FIG. 5C, an inhaled medicament deliverydevice 510 comprises a cartridge 549 and a reservoir tap 512. Thecartridge 549 includes a medicament 520 and a cartridge seal 544. Thereservoir tap 512 includes a tap shaft 553 and a nozzle 552. The tapshaft 553 is hollow and includes first ports 555 and second ports 556that, depending on the position of the reservoir tap 512 and theconfiguration of the cartridge seal 544, can allow liquids or gasses toflow from outside the reservoir tap 512, into the tap shaft 553, and outthe nozzle 552. The cartridge 540 may be separable and re-attachablefrom the inhaled medicament delivery device 510.

In FIG. 5C, the reservoir tap 512 is positioned in the same position asin FIG. 5A. In FIG. 5C, the tap shaft 553 penetrates the cartridge seal544 to an extent that it leaves the first ports 555 exposed to receivethe medicament 520, but due to the configuration of the cartridge seal544 does not expose the second ports 556 to receive the medicament 520.As shown by arrows 595, the first ports 555 (but not the second ports556) are exposed to such that the medicament 520 may enter a hollowinterior cavity of the tap shaft 553 and flow from the cartridge 540 tothe nozzle 553 under the force of a propellant. Since the configurationof the cartridge seal 544 only exposes the first ports 555 to themedicament 520 such that the medicament 520 can enter the hollowinterior cavity of the tap shaft 553, a lesser flow of the medicament520 is expected than if both of the first and second ports 555, 556 wereto allow the medicament 520 to enter the hollow interior cavity of thetap shaft 553 (as is illustrated in FIG. 5A for the same position of thereservoir tap 512).

As illustrated in FIG. 5C, even though the reservoir tap 512 is in thefirst activated position, the configuration of a seal 544 of thecartridge 549 only allows the medicament 520 to enter the ports 555travel down the tap shaft 553 to exit the nozzle 552 as the aerosolmixture 523. The aerosol mixture 523 may be further thermally modulatedand/or mixed with additional air by the inhaled medicament deliverydevice 510. The aerosol mixture 523 may correspond to, or be a precursorto, the mixture 121 and/or the mixture 221, described herein. Thus, itshould be understood that an aerosol mixture output by the nozzle 552can be controlled or affected by the position of the reservoir tap 512,the configuration of the cartridge 540, and both the position of thereservoir tap 512 and the configuration of the cartridge 540 (and theconfiguration of the seals 543 and/or the 544, in particular).

In an embodiment, a seal 544 is configured with a cavity 557. The cavity557 exists such that the second ports 556 are exposed to the cavity 557when the reservoir tap 512 is in the first activated position. Thecavity 557 may be pressurized with propellant, or exposed to outside airin order to help determine the composition of the mixture 523. Thecavity 557 may be pressurized with a gas to provide a positive flow ofgas before the medicament 520 begins to flow through the reservoir tap512. This positive flow of gas before the flow of the medicament 520begins may occur as the ports 555 pass (or stop) through the cavity 557on the way to being exposed to the medicament 520.

In an embodiment, the reservoir tap 512 comprises one or more the firstports 555 and the second ports 556 that open into the lumen of thereservoir tap 512. In one variation, the first ports 555 and the secondports 556 are in line with each other and are positioned along thelength of the reservoir tap 512. The first ports 555 and the secondports 556 may, for example, be identical in size or may, for example,have differing sizes. The first port 555 may, for example, be smallerthan the second port 556.

The dose of the medicament 520 delivered into the reservoir tap 512 maybe controlled by, for example, controlling the penetration of the nozzle552 to different depths within the cartridge 540. For example, when thereservoir tap 512 penetrates and passes through the cartridge seal 543to a certain depth, only the first port 555 is exposed within theinterior of the cartridge, while the second port 556 may remain embeddedwithin the interior of the seal 543 so that the seal 543 covers thesecond port 556, sealing it off. A deeper penetration exposing both thefirst port 555 and the second port 556 within the cartridge 540 wouldenable fluid to be ejected through the cartridge 540 at a faster rate.It should be understood, that the number of ports need not be limited totwo, but may also comprise, for example, three, four, five, or moreports along the reservoir tap 512. Similarly, it should be understoodthat the location and positon of the ports relative to each other may bevaried. For example, multiple ports may be located circumferentiallyalong the reservoir tap 512. For example, the ports need not be in linewith each other but can be spaced apart at variable distances from eachother. Similarly, various shapes are usable for the ports including, forexample, circular, ellipsoidal, and polygonal shapes. Similarly, thereare other means known to those having skill in the art for selectivelysealing off the ports aside from covering one or more of the portswithin the cartridge seal 543. For example, the reservoir tap 512 maymove slideably within a housing capable of selectively blocking offports depending on the distance traveled by the slideable reservoir tapwithin the housing. In another example a variable rate flow controllervalve could be used to selectively control the flow of liquid or gasesor medicament 520 from the cartridge 540.

The reservoir tap 512 may be advanced into and through the cartridgeseal 544 with, for example, a spring driven mechanism. The reservoir tap512 may be advanced into and through the seal 543 with, for example, amanually driven mechanism. Any known mechanism that advances thereservoir tap 512 into and though the cartridge seal 543 is suitable.

FIGS. 6A-6C show an embodiment in which a reservoir tap 612 is driven bya magnetic actuator under the control of a controller 611. In FIGS.6A-6C, the inhaled medicament delivery device 610 comprises a cartridge640, a controller 611, an actuator 662, a magnet 661, and a reservoirtap 612. The cartridge 640 includes a medicament 620, and a cartridgeseal 643. The reservoir tap 612 includes a tap shaft 653 and a nozzle652. The tap shaft 653 is hollow and includes ports 655 and ports 656that allow liquids or gasses to flow from outside the reservoir tap 612,into the tap shaft 653, and out the nozzle 652. The cartridge 640 may beseparable and re-attachable from the inhaled medicament delivery device610.

The actuator 662 is operatively coupled to the controller 611. Theactuator 662 is under the control of the controller 611, whichselectively attracts or repels the magnet 661. The magnets 661 areattached to the reservoir tap 612 such that, as the actuator 662attracts or repels the magnet 661 to apply a force to the magnets 661,the reservoir tap 612 moves with the magnets 661. The actuator 662 isattached to the inhaled medicament delivery device 610, but not thereservoir tap 612, such that the reservoir tap 612 may slideably moveproximally and distally with respect to the cartridge 640. The reservoirtap 612 may, under the control of the controller 611, slideably moveproximally and distally with respect to the cartridge 640 in order toposition the reservoir tap 612 such that the ports 655 and/or 656 may becontrollably positioned to receive the medicament 620.

FIG. 6A illustrates the actuating of the reservoir tap 612 by thecontroller 611 (via the interaction of the actuator 662 and the magnets661) to a first (inactive) position. In the first position illustratedin FIG. 6A, the ports 655 are occluded by the seal 643. The ports 656are positioned more proximally along the tap shaft 653 than the ports655. Thus, the ports 656 are positioned such that they are not capableof receiving the medicament 620.

FIG. 6B illustrates the actuating of the reservoir tap 612 by thecontroller 611 (via the interaction of the actuator 662 and the magnets661) to a second (active) position. In the second position illustratedin FIG. 6B, the reservoir tap 612 has been displaced by the controller611 to a position more distal than illustrated in FIG. 6A. The ports 655are exposed to receive the medicament 620. The ports 656 are occluded bythe cartridge seal 643. Thus, the ports 656 are positioned such thatthey are not capable of receiving the medicament 620.

FIG. 6C illustrates the actuating of the reservoir tap 612 by thecontroller 611 (via the interaction of the actuator 662 and the magnets661) to a third (active) position. In the third position illustrated inFIG. 6C, the reservoir tap 612 has been displaced by the controller 611to a position more distal than illustrated in FIG. 6B. The ports 655 and656 are exposed to receive the medicament 620. Accordingly, it should beunderstood that the controller 611 may dynamically move the reservoirtap 612 in order to allow medicament 620 to flow or not flow through thereservoir tap 612 (and thereby generate an aerosol). The controller 611may dynamically move the reservoir tap 612 in order to modulate the flowof the medicament 620 through the reservoir tap 612 (and thereby controlthe mixture of a generated aerosol).

FIG. 7 illustrates controlled thermal heating of a reservoir tap. InFIG. 7, an inhaled medicament delivery device 710 comprises a cartridge740, a controller 711, an actuator 762, a magnet 761, a heater 713, anda reservoir tap 712. The cartridge 740 includes a medicament 720, and acartridge seal 743. The reservoir tap 712 includes a tap shaft 753 and anozzle 752. The tap shaft 753 is hollow and includes ports 755 and 756that allow liquids or gasses to flow from outside the reservoir tap 712,into the tap shaft 753, and out the nozzle 752. The cartridge 740 may beseparable and re-attachable from the inhaled medicament delivery device710.

The actuator 762 is operatively coupled to the controller 711. Theheater 713 is operatively coupled to the controller 711. The actuator762, under the control of the controller 711, selectively attracts orrepels the magnet 761. The magnets 761 are attached to the reservoir tap712 such that as the actuator 762 attracts or repels the magnet 761 toapply a force to the magnets 761, the reservoir tap 712 moves with themagnets 761. The actuator 762 is attached to the inhaled medicamentdelivery device 710, but not the reservoir tap 712, such that thereservoir tap 712 may slideably move proximally and distally withrespect to the cartridge 740. The reservoir tap 712 may, under thecontrol of the controller 711, slideably move proximally and distallywith respect to the cartridge 740 in order to position the reservoir tap712 such that the ports 755 and/or 756 may be controllably positioned toreceive the medicament 720.

FIG. 7 illustrates the actuating of the reservoir tap 712 by thecontroller 711 (via the interaction of the actuator 762 and the magnets761) to an inactive position. It should be understood, however, that thecontroller 711 can position the reservoir tap 712 in various activepositions as well as dynamically moving the reservoir tap 712 during anactivation cycle. In the position illustrated in FIG. 7A, the ports 755are occluded by the cartridge seal 743. The ports 756 are positionedmore proximal along the tap shaft 753 than the ports 755. Thus, in FIG.7, the ports 756 are positioned such that they are not capable ofreceiving the medicament 720.

The controller 711 is operatively coupled to the heater 713. The heater713 may be an inductive heater. In an embodiment, the heater 713 maymove with the reservoir tap 712 as the reservoir tap 712 is slideablypositioned and/or moved. Thus, the actuation of the reservoir tap 712does not change the portion(s) of the reservoir tap 712 being heated bythe heater 713. In another embodiment, the heater 713 remains stationarywith respect to the cartridge 740. Thus, the actuation of the reservoirtap 712 changes the portion(s) of the reservoir tap 712 (and the tapshaft 753, in particular) being heated by the heater 713.

FIG. 8 is a chart illustrating medicament flow rate. In FIG. 8, curve801 illustrates an exemplary relative airflow rate versus time. Curve801 may represent the airflow generated during an inhalation cycle of asubject operating an inhalable medicament delivery device. Curve 802illustrates an exemplary relative displacement (i.e., position) of areservoir tap. As can be seen in FIG. 8, the reservoir tap starts at afirst position with little or no displacement. In other words, thereservoir tap starts in an inactive position. As the airflow shown bycurve 801 increases over time, the reservoir tap is repositioned to afirst active position. The reservoir tap remains in this first activeposition for a first period of time during the inhalation cycle. At asecond point in the inhalation cycle, the reservoir tap is repositionedto a second active position. The reservoir tap remains in this secondactive position for a second period of time during the inhalation cycle.At a third point in the inhalation cycle, the reservoir tap isrepositioned to a third active position. The reservoir tap remains inthis third active position for a third period of time during theinhalation cycle. Finally, the reservoir tap is repositioned to aninactive position.

Curve 803 illustrates an exemplary medicament flow rate through areservoir tap. As can be seen in FIG. 8, the inhalation cycle startswith little or no medicament flow. This may be the result of thereservoir tap starting in an inactive position. As the airflow shown bycurve 801 increases over time, the medicament flow is set to a firstamount by the repositioning of the reservoir tap to the first activeposition. The medicament flow remains set to the first amount for afirst period of time during the inhalation cycle. At a second point inthe inhalation cycle, the reservoir tap is repositioned to a secondactive position. This sets the medicament flow to a second amount for asecond period of time during the inhalation cycle. When the reservoirtap is repositioned to the third position at the third point in theinhalation cycle, the medicament flow is reduced to little or none.Thus, during the third period of time during the inhalation cycle, onlyair is flowing to a subject.

FIG. 9A is an illustration of an embodiment comprising a medicamentcartridge with a reservoir and propellant tap for an inhaled medicamentdelivery device. In FIG. 9A, a cartridge valve assembly that mates tothe tap shaft is used instead of a tap shaft that penetrates a seal,wherein the tap shaft is, for example, a component of a cartridge thatacts as a valve.

FIG. 9B shows an enlarged illustration of an embodiment of a medicamentcartridge with a valve assembly. In FIG. 9B, an inhaled medicamentdelivery device 910 comprises a cartridge 940 and a nozzle assembly 912.The cartridge 940 includes a bladder 944, a medicament 920, a seal 943,a seal 946, a valve shaft 954, a propellant 941, and a return spring992. The nozzle assembly 912 includes a shaft 953 and a nozzle 952. Theshaft 953 is hollow and is configured to mate with the valve shaft 954.The bladder 944 holds the medicament 920.

The valve shaft 954 includes ports 955 and ports 956 that allow liquidsor gasses to flow from the cartridge 940, into the valve shaft 954, intothe shaft 953, and out the nozzle 952. In particular, when the valveshaft 954 is moved by the shaft 953 in an active position (i.e., isactivated), the propellant 941 gas may flow into one of more of theports 955, through the valve shaft 954 into the shaft 953, and then outthe nozzle 952. Likewise, when the valve shaft 954 is moved by the shaft953 in an active position (i.e., is activated), the medicament 920 mayflow out of the bladder 944 into one or more of the ports 956, throughthe valve shaft 954 into the shaft 953, and then out the nozzle 952.

In an embodiment, the bladder 920 has an opening that is occluded by thevalve shaft 954 when the valve shaft 954 is in the non-activatedpositon. When, the valve shaft 954 is in the activated position, theopening in the bladder 944 aligns with the ports 956 on the valve shaft954 so that the contents of the bladder 944 may flow into the ports 956.

When activated, the shaft 953 pushes the valve shaft 954 into anactivated position within the cartridge 940. When deactivated, thereturn spring 992 pushes the valve shaft 954 back to an inactiveposition. When deactivated, the valve shaft 954 is positioned such thatthe seal 943 occludes the ports 956 and the seal 946 occludes the ports955, thereby preventing the propellant 941 and the medicament 920 fromentering the valve shaft 954. When activated, the shaft 953 pushes thevalve shaft 954 into an activated position. In an activated position,one or more of the ports 955 and/or 956 are not occluded.

For example, the valve shaft 954 can be pushed into a position wherebyone or more of the ports 955 are exposed to the propellant 941, but theports 956 are occluded. In this position, only the propellant 941 wouldbe ejected from the nozzle 952. In another example, the valve shaft 954is pushed into a position whereby the ports 955 are occluded, but theports 956 are receiving the medicament 920 from the bladder 944. In thisposition, only the medicament 920 would be provided to the nozzle 952.In another example, the valve shaft 954 is pushed into a positionwhereby one or more of the ports 955 are exposed to the propellant 941,and the ports 956 are position to receive the medicament 920 from thebladder 944. In this position, both the medicament 920 and thepropellant 941 are provided to the nozzle 952.

The cartridge 940 may be separable and re-attachable from the inhaledmedicament delivery device 910. The compressible bladder 944 ispreferably positioned proximally to the cartridge 940 comprising thepressurized gaseous propellant 941. In an embodiment, the bladder 944may be distensible and exert a pressure on the liquid wholly orpartially (in conjunction with the pressurized gas) to drive the liquidinto the nozzle 952.

In an embodiment, the bladder 944 may comprise a plurality of layers,such that between the inner bladder 944 which contains the liquidmedicament 920 and the outer bladder 944 there is a space that couldcontain dry neutralizing agent or absorbent material to render theactive excipient inactive or to otherwise absorb and capture the activeexcipient, a liquid neutralizing agent could also be contained in thespace between the outer surface of the inner bladder 944 and the innersurface of the outer bladder 944. The bladder 944 allows for the deviceto be activated in a fashion that is independent of the orientation inspace of the inhaled medicament delivery device 910.

FIG. 9C is an illustration of the activation of a medicament cartridge940 with a reservoir and a propellant tap. As illustrated in FIG. 9C,the valve shaft 954 is positioned such that the ports 955 are exposed tothe propellant 941 and one or more ports 956 are positioned to receivethe medicament 920 from the bladder 944. As shown by arrows 993, thepropellant 941 enters at least one of ports 955 and the medicament 920enters at least one of the ports 956. The propellant 941 and themedicament 920 then flow through the valve shaft 954, the shaft 953, andexit the nozzle 952 as an aerosol mixture 921.

In an embodiment, a flow rate is determined by an inhalable medicamentdelivery device. In an embodiment, the type of port that is positionedwithin the cartridge is selected to control or determine the flow rateof the medicament through the device. In an embodiment, airflowamplifying features that utilize the Coanda and/or Venturi effects areutilized selectively to generate increases in flow rate and/or amounts.In an embodiment, a valve system is configured to selectively cover andexpose the openings on various ports of different sizes in order tocontrol the flow of medicament through the device. In an embodiment, aflow rate of a medicament delivered by a medicament delivery devicecomprises about the same flow rate as a flow rate of a medicamentdelivered by a jet nebulizer. In an embodiment, a flow rate of amedicament delivered by a medicament delivery device comprises about thesame flow rate as a flow rate of a medicament delivered by a standardinhaler or metered dose inhaler. In an embodiment, a flow rate of amedicament delivered by a medicament delivery device comprises about thesame flow rate as the flow of smoke or aerosol delivered by a cigarette.

FIG. 10A is an exterior view of an embodiment of an inhaled medicamentdelivery device. In FIG. 10A, the inhaled medicament delivery device1010 comprises a main body 1017, a cartridge cover 1018, a mouthpiececover 1081, a display 1082, a primary button 1083, and secondary buttons1084. The main body 1017 and the cartridge cover 1018 may be comprisedof different material such as metals, alloys, plastics, polymers,ceramics, or a combination of such materials. The main body 1017 and thecartridge cover 1018 are illustrated as having a cubic or square orrectangular shape, however, other shapes for are possible such ascylindrical, elliptical, ovoid, or the like. The mouthpiece cover 1081is located on the most proximal aspect of the inhaled medicamentdelivery device 1010 for engaging a subject's lips to form a seal suchthat the subject may inhale a vaporized aerosol from the inhaledmedicament delivery device 1010 into the mouth, airways, and lungs. Themouthpiece cover 1081 may be comprised of silicon, rubber, plastic,polymer, ceramic, metal, or other materials. The mouthpiece cover 1081may be comprised of materials that resist or impede the growth ofbacteria, such as materials comprised of or containing antimicrobialagents. The mouthpiece cover 1081 may be configured to be easilyremovable and replaceable by the subject such that the mouthpiece cover1081 may be exchanged for a new mouthpiece cover 1081. The mouthpiececover 1081 may be disposable or reusable. The mouthpiece cover 1081 maybe of a material that can be sanitized with sanitizing agents such asalcohol or similar agents. The mouthpiece cover 1081 may be cleaned byheat sanitization such as boiling in water or through the application ofsteam.

The inhaled medicament delivery device 1010 is intended to be operatedby the subject using a single hand. The inhaled medicament deliverydevice 1010 can be operated by bringing the mouthpiece cover 1081 to thelips and activating the inhaled medicament delivery device 1010 throughthe use of the primary button 1083 (illustrated), a switch, sensor,and/or a combination. The cartridge cover 1018 serves as a cover housinga cartridge. The cartridge cover 1018 and the main body 1017 comprisethe majority of the outer surface of the inhaled medicament deliverydevice 1010.

FIG. 10B illustrates an exploded view of an embodiment of an inhaledmedicament delivery device 1010. In FIG. 10B the parts of inhaledmedicament delivery device 1010 illustrated include the reservoir tap1012, the cartridge cover 1018, a valve assembly 1050, a battery andelectronics assembly 1011, a main body 1017, and a mouthpiece cover1081.

FIG. 10C illustrates an exploded view of an embodiment of a cartridgecover 1018 and a cartridge 1040 for an inhaled medicament deliverydevice 1010. In FIG. 10C, the parts of the inhaled medicament deliverydevice 1010 illustrated include the cartridge cover 1018 and thecartridge 1040. The cartridge 1040 includes a cartridge filling plug1041. The cartridge filling plug 1041 allows the cartridge 1040 to berefilled with medicament, propellant, or both. In an embodiment, theremay be more than one cartridge filling plug 1041.

FIG. 10D illustrates an exploded view of an embodiment of a cartridge1040 for an inhaled medicament delivery device 1010. In FIG. 10D, theparts of the cartridge 1040 illustrated include a cartridge filling plug1041, a gas cartridge 1049, a porous reservoir 1042, a septum retainer1047, a septum 1043, and a cartridge septum housing 1048.

The gas cartridge 1049 may hold a gas propellant such as carbon dioxide(CO₂). The gas is held in the cartridge 1040 under pressure such as toprovide a positive pressure that drives a liquid formulation in thecartridge 1040 out of the cartridge 1040 through a nozzle to generate anaerosol. Interior to the gas cartridge 1049 is the porous reservoir 1042that occupies the distal area of the cartridge 1040. The porousreservoir 1042 serves to hold, retain, or otherwise trap a liquidformulation in such a manner that the gas held in the cartridge 1040 isforced through the porous reservoir 1042, and as a result, displaces theliquid out of the porous reservoir 1042 for delivery to a hollow nozzleshaft and then to a nozzle.

The porous reservoir 1042 could be comprised of porous or matrixmaterials that are hydrophobic and have the capability of retaining theliquid formulation through capillary action or similar means in voidspaces in the matrix or pores in the porous material. Materials such asceramics, glasses, polymers, or plastics may be suitable for theapplication. The porous reservoir 1042 may allow for the inhaledmedicament delivery device 1010 to be operated regardless of orientationas the porous reservoir 1042 containing the liquid formulation maintainsthe liquid formulation in a proximal orientation to an outlet port. Theporous reservoir 1042 may be omitted in some embodiments where theliquid formulation is brought into a miscible solution with a gaseouspropellant.

The porous reservoir 1042 may contain encapsulated absorbents orneutralizing agents (not illustrated in FIGS. 10A-10L) such as toprevent intentional or unintentional access or contact with a liquidformulation. An encapsulated absorbent such as charcoal can be encasedin a hydrophobic casing such as a plastic, polymer, ceramic, or glasssuch that if the cartridge 1040 was accessed and the porous reservoir1042 was removed, the encapsulation would rupture or otherwise allow theabsorbent or neutralizing agent to come into contact with the liquidformulation and render the liquid formulation inaccessible orfunctionally neutralized.

The cartridge 1040 may be sealed at the proximal aspect by the cartridgeseptum housing 1048 that also engages with the septum 1043. The septum1043 is comprised of a malleable material such as a silicon rubber orsimilar. In an embodiment, the septum 1043 is comprised of aself-healing material such as a silicon plug. The self-healing materialallows for a nozzle shaft to slide in the proximal to distal respect andenter the cartridge 1040. When the inhaled medicament delivery device1010 is not in use, a port or ports present on the lateral aspect of thenozzle shaft are occluded or otherwise blocked by the septum 1043. Thisorientation functionally seals the cartridge 1040 such that the liquidformulation cannot escape the cartridge 1040.

FIGS. 10E and 10F illustrate exploded views of an embodiment of areservoir tap 1012 assembly for an inhaled medicament delivery device1010. The parts of the reservoir tap 1012 illustrated include a nozzle1052, a tap shaft 1053, ports 1055, ports 1056, and magnets 1061. Thereservoir tap 1012 may be disposed in a sleeve 1059 to allow slideablemovement in the proximal and distal directions. The tap shaft 1053includes a hollow cavity that allows fluid to flow from the ports 1055and/or 1056 to the nozzle 1052. The magnets 1061 may interact with anactuator in order to move or position the reservoir tap 1012 relative tothe septum 1043 and the cartridge 1040.

FIG. 10G illustrates an exploded view of an embodiment of a valveassembly 1050 for an inhaled medicament delivery device 1010. In FIG.10G, the parts of the valve assembly 1050 illustrated include a valvehousing lid 1067, a printed circuit board (PCB) 1066, a valve housing1065, an electronic module 1069, and a capacitor 1068. In an embodiment,the capacitor 1068 is a supercapacitor.

FIG. 10H illustrates an exploded view of an embodiment of a battery andelectronics assembly 1011 for an inhaled medicament delivery device1010. In FIG. 10G, the parts of the battery and electronics assembly1011 illustrated include a controller 1087, heater contacts 1088, abattery 1085, and a housing 1086. The heater contacts 1088 areelectrically coupled to the controller 1087. In an embodiment, theheater contacts 1088 include a plurality of heater contacts 1088 thatallow for the selective activation of separate heating elements by thecontroller 1087.

FIG. 11 illustrates an exploded view of an embodiment of a cartridge foran inhaled medicament delivery device. In FIG. 11, the parts of acartridge 1140 illustrated include a cartridge filling plug 1145, a gascartridge 1149, a bladder 1144, a septum retainer 1147, an outer septum1143, an inner septum 1173, a septum separator 1174, and a cartridge lid1148.

FIG. 12 illustrates an exploded view of an embodiment of an inhaledmedicament delivery device 1210. In FIG. 12 the parts of the inhaledmedicament delivery device 1210 illustrated include a cartridge 1140, avalve assembly 1050, a reservoir tap 1012, an aspiration tube 1219, aheat reflector 1218, heater segments 1213,1214, 1215, and 1216, abattery and electronics assembly 1011, a display 1082, and a mouthpiececover 1081.

In an embodiment, an aerosol generated by the nozzle of the reservoirtap 1012 enters the aspiration tube 1219, which is circumferential tothe nozzle. The aspiration tube 1219 conducts the generated aerosol tothe mouthpiece. The aspiration tube 1219 may be heated partially orthroughout the length of the aspiration tube 1219 by heater segments1213-1216. The degree of heating along the length of the aspiration tube1219 may be modulated as to optimize the vaporization or thermalmodulation of the aerosol to achieve the desired particle size fordelivery of the medicament to the lungs or other desired airway region.In an embodiment, the aspiration tube 1219 is heated from the outersurface of the tube by one or more of heater segments 1213-1216 suchthat the aerosol does not come into contact directly with the heatingelement or elements. The reflector 1218 help focus thermal energy intothe aspiration tube 1219.

The aspiration tube 1219 may be comprised of ceramic, glass, metals,alloys or other suitable materials. The aspiration tube 1219 may beheated by a separate tube containing heater segments or otherwiseradiating heat and/or infrared radiation. Thus, the aspiration tube 1219may be considered to be a black body absorber of heat and/or infraredradiation.

The heater segments 1213-1216 may be comprised of a coil, or be printed,plated, or otherwise directly applied or affixed to the inner or outersurface of the aspiration tube 1219, or be contained within the wall ofaspiration tube 1219. The heater segments 1213-1216 may be isolated fromthe aspiration tube by a thin covering or coating of material that maybe the same material composition of the aspiration tube 1219 or anothersuitable material such as a glass or ceramic coating, such that theaerosol does not directly contact the heater element material, or suchthat the heater element material is encased by the coating material suchthat the heater material cannot be released into the aerosol or reactwith the aerosol. The heater segments 1213-1216 may generate heatthrough a variety of methods. In an embodiment, the heat is generatedthrough the emission or generation of infrared energy. In an embodiment,the aspiration tube 1219 is comprised of a material that reduces thermalloss from the heating element or elements by reflecting or otherwisereducing the loss of thermal energy, such as infrared energy, throughthe selection of materials that reflect the infrared energy into theaspiration tube 1219. In an the reflector 1218 is comprised of amaterial that reduces thermal loss from the heating element or elementsby reflecting or otherwise reducing the loss of thermal energy, such asinfrared energy, through the selection of materials that reflect theinfrared energy into the aspiration tube 1219.

FIG. 13 illustrates a block diagram of an embodiment of a computersystem. The controllers 211, 611, and/or 711 may be or include acomputer system. Computer software may implement one or more of thecontrol functions and/or display functions described herein. A computersystem 1300 includes a communication interface 1320, a processing system1330, a storage system 1340, and a user interface 1360. The processingsystem 1330 is operatively coupled to the storage system 1340. Thestorage system 1340 stores software 1350 and data 1370. The processingsystem 1330 is operatively coupled to the communication interface 1320and the user interface 1360. The computer system 1300 may comprise aprogrammed general-purpose computer. The computer system 1300 mayinclude a microprocessor. The computer system 1300 may compriseprogrammable or special purpose circuitry. The computer system 1300 maybe distributed among multiple devices, processors, storage, and/orinterfaces that together comprise elements 1320-1370.

The communication interface 1320 may comprise a network interface,modem, port, bus, link, transceiver, or other communication device. Thecommunication interface 1320 may be distributed among multiplecommunication devices. The processing system 1330 may comprise amicroprocessor, microcontroller, logic circuit, or other processingdevice. The processing system 1330 may be distributed among multipleprocessing devices. The user interface 1360 may comprise a keyboard,mouse, voice recognition interface, microphone and speakers, graphicaldisplay, touch screen, or other type of user interface device. The userinterface 1360 may be distributed among multiple interface devices. Thestorage system 1340 may comprise a disk, tape, integrated circuit, RAM,ROM, EEPROM, flash memory, network storage, server, or other memoryfunction. The storage system 1340 may include computer readable medium.The storage system 1340 may be distributed among multiple memorydevices.

The processing system 1330 retrieves and executes the software 1350 fromthe storage system 1340. Processing system 1330 may retrieve and storedata 1370. The processing system 1330 may also retrieve and store data1370 via the communication interface 1320. The processing system 1330may create or modify software 1350 or data 1370 to achieve a tangibleresult. The processing system 1330 may control communication interface1320 or user interface 1360 to achieve a tangible result. The processingsystem 1330 may retrieve and execute remotely stored software via thecommunication interface 1320.

The software 1350 and remotely stored software may comprise an operatingsystem, utilities, drivers, networking software, and other softwaretypically executed by a computer system. The software 1350 may comprisean application program, applet, firmware, or other form ofmachine-readable processing instructions typically executed by acomputer system. When executed by the processing system 1330, thesoftware 1350 or remotely stored software may direct the computer system1300 to operate.

In an embodiment, an inhalable medicament delivery device comprises apower module. In an embodiment, a power module comprises a CPU, aprocessor, and at least one sensor.

In an embodiment, an inhalable medicament delivery device comprises oneor more temperature sensors. In an embodiment, one or more temperaturesensors are coupled to a processor that is configured to receivetemperature data form the one or more sensors. In an embodiment, theprocessor is further configured to modify a temperature of one or moreheaters in response to temperature data received from one or morethermal sensors.

In an embodiment, an inhalable medicament delivery device comprises oneor more sensors configured to sense ambient data. In an embodiment, asensor is configured to sense ambient temperature. In an embodiment, asensor is configured to sense an ambient pressure. In an embodiment, asensor is configured to sense an oral temperature of a subject. In anembodiment, one or more sensors configured to sense ambient data arecoupled to a processor. In an embodiment, a processor is furtherconfigured to modify a temperature of one or more heaters in response totemperature or pressure data received from one or more ambient sensors.In an embodiment, a processor is configured to calibrate and adjust thedevice in response to environmental factors that may be measured by oneor more ambient sensors.

In an embodiment, an inhalable medicament delivery device comprises oneor more flow sensors. In an embodiment, one or more flow sensors sense aflow rate of a medicament as the medicament travels through theinhalable medicament delivery device. In an embodiment, one or moresensors configured to sense flow rate data are coupled to a processor.In an embodiment, a processor is further configured to modify atemperature of one or more heaters in response to flow rate datareceived from one or more flow sensors. In an embodiment, a processor isfurther configured to modify a flow rate in response to flow rate datareceived from a flow rate sensor. For example, in response to flow ratedata received from a flow sensor, a processor may cause a second port tobe advanced into the cartridge, thus increasing the medicament flow ratethrough the nozzle and aspiration tube as described herein. For example,in response to flow rate data received from a flow sensor, a processormay cause a second port to be withdrawn out of the cartridge, thusdecreasing the medicament flow rate through the nozzle and aspirationtube as described herein.

In an embodiment, an inhalable medicament delivery device comprises oneor more biometric sensors. In an embodiment, one or more biometricsensors are configured to identify a subject. In an embodiment, one ormore biometric sensors are coupled with a processor. In an embodiment, aprocessor is further configured to activate an inhalable medicamentdevice only if a biometric sensor provides a signal comprising aconfirmation of an identity of a subject.

In an embodiment, use of the inhalable medicament delivery devicecomprises one or more of the following steps: A subject obtains aninhalable medicament device. In a variation, the inhalable medicamentdevice is configured, ahead of use, to provide a particular medicamentto a subject in a particular fashion. In a variation, the inhalablemedicament delivery device is configured so that one or more of a flowrate, temperature, and aerosol particle size of a medicament to bedelivered to a patient is set before the device is used. In a variation,one or more biometric sensors confirm an identity of a subject, andallow the inhalable medicament delivery device to be activated inresponse to confirming the identity of a subject through the biometricsensor. In a variation, comprising of an embodiment wherein thecartridge and housing are separate components, a subject couples acartridge containing a medicament to a housing of the inhalablemedicament delivery device. In a variation, a subject places themouthpiece of the device either against his lips or close to his mouth.In a variation, a subject presses a button or touches a touch screenthat causes the ejection of the medicament from the cartridge anddelivery of the medicament of the subject through the aspiration tube.In a variation, a subject controls the flow rate of the deliveredmedicament through a user interface. In a variation, after use thedevice is configured to self-sterilize, by, for example, heating theaspiration tube.

Compositions

In an embodiment, an aerosolized medicament generated by an inhaledmedicament delivery device may comprise droplets or may be mixed withvapor forming an aerosol and vapor mixture. Alternatively, theaerosolized medicament may be entirely vaporized within the device.

An aerosol typically comprises liquid droplets suspended in a gas. Theliquid droplets within the aerosol generated by the inhaled medicamentdelivery device, as described herein, comprises medicament particles andmay further comprise an excipient. The aerosol generated by the devicemay be further converted to a vapor by, for example, heating theaerosol. The term “vapor” may be understood to mean the gaseous form ofthe aerosol. An aerosol may be, for example, heated to a degree whereinthe aerosol is partially converted to a vapor, and partially remains anaerosol, thus forming an aerosol and vapor mixture. The droplets withinthe aerosol will typically comprise larger medicament particles than theparticles of medicament found within the vapor. The aerosol droplet orparticle size, as well as the degree of vaporization, affects thedelivery of the medicament.

The droplet sizes within an aerosol or partial vapor may be modified toaffect medicament delivery in a predictable way. That is, droplet sizecan be increased or decreased by modulating the temperature within theaerosol-generating device. Large and small aerosol droplets traveldifferently, which allows control over medicament delivery through themodulation of aerosol droplet size. For example, larger particles tendnot to travel as deeply into the airway and lung as smaller particles.Also, larger particles, when too large, may be expelled. Thus, forexample, if delivery of medicament primarily to the upper airways andupper lung lobes were desired, a larger droplet size would be optimal.Alternatively, smaller particles tend to travel deeper in the lungs, andso a smaller droplet or vapor would be optimal for delivery to the lowerlung lobes. However, very small droplets travel deep into the lung andare then subsequently exhaled without being absorbed.

One useful way to describe the size of particles within an aerosol isusing the Mass Median Aerodynamic Diameter (MMAD) of the particles. TheMMAD is equal to the diameter of a particle of average mass of apopulation. Meaning, the MMAD is the diameter of a particle for which50% of the aerosol mass is greater in mass than the mass of thatparticle and the 50% is smaller in mass than the mass of that particle.Three different mechanisms can be used to describe aerosol deposition.The three mechanisms are impaction, sedimentation, and suspension. Inimpaction, particles of an aerosol tend to continue on a trajectory whenthey travel through the airway, instead of conforming to the curves ofthe respiratory tract. Particles with enough momentum are affected bycentrifugal force at the points where the airflow suddenly changesdirections, colliding with the airway wall. Impaction mainly affectsparticles larger than 10 μm. Particles larger than 10 μm may tend todeposit in the oropharynx. In sedimentation, particles with sufficientmass are deposited due to gravity when they remain the airway for asufficient length of time. Lastly, in suspension, the particles of anaerosol move erratically from one place to another in the airways, as aconsequence of Brownian diffusion. Suspension tends to affect particleswith a smaller MMAD than 0.5 μm in the alveolar spaces wherein airspeedis practically zero. Particles with a smaller MMAD than 0.5 μm aretypically not deposited and are expelled upon exhalation.

Particles with, for example, a MMAD between 10-15 μm may tend to bedeposited in the oropharynx. Particles with, for example, a MMADmeasuring between 5 and 10 μm may tend to be deposited in the upperairways. Particles with, for example, a MMAD from 0.5 to 5 μm may tendto be deposited in the lower airways and alveoli. Respiratory treatmentto be delivered to the alveoli may thus be achieved using particles withan MMAD between 0.5 and 5 μm. The range of 0.5 and 5 μm is known as thebreathable fraction of an aerosol. (Tena, F., Casan Clara, P. Depositionof Inhaled Particles Within the Lungs. Arch Bronconeumol. 2012;48(7):240-246).

An inhaled medicine intended to penetrate deeply into the lung may, forexample, be designed to deliver aerodynamic particle sizes between 0.1and 5 μm. As above, particle sizes that are too small, for example, <0.1μm, may result in low deposition due to a high amount exhaled, whereaslarger particles may be deposited to an increasing extent in the upperand central airways. A larger particle size may, however, be optimal foran inhaled medicine targeting, for example, the tracheobronchial region.

In terms of deep penetration of a delivered medicament into the lung,hygroscopic effect may also be a consideration. Generally,hygroscopicity is the property of some substances to absorb and exhalehumidity depending on the setting in which they are found. This meansthat a hygroscopic particle can grow larger or smaller in size uponentering into a moist airway, with the consequent modification in thedeposition pattern compared to what was initially expected, due to theincrease in particle size from hygroscopic effect. That is, a particlemay start within a size range that would predict delivery into thealveoli, and due to hygroscopic effect, grow to a size that would makealveolar delivery unlikely. The particle size of an inhaled medicamenttends to increase as the inhaled medicament travels through the mouth,oropharynx, and lower respiratory tract of a subject due to, forexample, heating of the inhaled medicament. As mentioned above,different size particles travel more efficiently to different portionsof the lung. Thus, a medicament can be delivered in submicron partial orcomplete vapor form so that it will increase inside the pulmonary tractto an optimal or target size. The growth of the particle to the optimalor target particle size within the respiratory tract ensures optimaldelivery of medicament to the portion of the lung that most efficientlyreceives particles of that size.

Thus, for example, for effective deposition of a particle with the finaldiameter of 3.5 μm, it may be necessary to compensate for hygroscopiceffect by delivering a particle of, for example, 0.5 μm with theexpectation that it will grow towards a diameter of 3.5 μm whiletraveling through the oropharynx and airway. (Zarogouldis, P., et al.Vectors for Inhaled Gene Therapy in Lung Cancer Application for NanoOncology and Safety of Bio Nanotechnology. Int. J. Mol. Sci. 2012, 13,10828-10862). In general, it is considered that hygroscopic growth maynot have much of an effect on particles with a MMAD of less than 0.1 μm;meanwhile hygroscopic effect may be more noticeable in particles with aMMAD larger than 0.5 μm.

The partial or complete vapor of the inhalable medicament providesadvantages in terms of delivery of medicament to the lungs and pulmonaryvasculature. Smaller particles as, for example, found in a vapor, tendto travel farther through the respiratory tract as compared to anaerosol, because the vapor is, for example, lighter, and, for example,tends to be absorbed to a lesser degree by the proximal tissue of theoropharynx. Generally, the smaller the particle size the further it willpenetrate into the respiratory tract, meaning larger particles tend tobe delivered most optimally towards the lung apices, midsized particlestend to be best delivered to the mid-lung, and vapor or small particlestend to be delivered best to the lung bases.

Vaporization of the aerosolized medicament is advantageous because, forexample, it increases the degree of drug delivery into the lung by, forexample, increasing the degree of medicament penetration into the lung.Furthermore, due to its increased gaseous volume of a vapor relative toan aerosol, a vapor provides for better distribution of the medicamentthroughout the lung tissue relative to an aerosol. Better distributionof the medicament throughout the lung tissue, for example, leads to moreeven distribution of the medicament in pulmonary vasculature once themedicament is absorbed. More even distribution of the medicament in thepulmonary vasculature may, for example, lead to more efficientmedicament delivery of a vapor or partial vapor as compared to anaerosol.

A further advantage of vaporization is a decrease or elimination oftracheal and oropharyngeal stimulation with inhalation of a medicament.When exposed to foreign material, the trachea and oropharynx may bestimulated in a way that would, for example, induce a cough reflex,cause an unpleasant sensation, or decrease the degree of inhalation.Stimulation of the cough reflex may prevent effective delivery of aninhaled medicament when the subject coughs. Because the particles in avapor are extremely small, there is decreased or eliminated tracheal andoropharyngeal stimulation with the use of a vapor or partial vapor ascompared to larger droplets.

Particle Size Distribution

The devices disclosed herein allow for a controlled and reproducibleparticle size distribution of the aerosol generated. As mentionedpreviously, the aerosol particle size distribution is related to theamount of heat applied to the aerosol, or the temperature of which theaerosol is heated at upon generation. Controlling the amount of heatapplied to the aerosol, or the temperature at which the aerosol isheated, allows for a tighter particle size distribution of the aerosolgenerated.

Provided herein is a method of delivering an inhaled medicament to asubject, comprising generating an aerosol from the inhaled medicamentand heating an aerosol at specific temperature range of about 100° C. toabout 285° C. to provide a particle size distribution of the aerosolgenerated of about 0.1 μm to about 15 μm, wherein the aerosol isdelivered to a specific target site of the subject.

Also provided herein is a method of delivering an inhaled medicament toa subject for nicotine replacement therapy comprising generating anaerosol from the inhaled medicament and heating an aerosol at specifictemperature range of about 130° C. to about 200° C. to provide aparticle size distribution of the aerosol generated of about 0.1 μm toabout 15 μm, wherein the aerosol is delivered to a specific target siteof the subject.

In some embodiments, the specific temperature range is about 150° C. toabout 175° C. to provide a particle size distribution of the aerosolgenerated of about 0.1 μm to about 15 μm. In some embodiments, thespecific temperature range is about 150° C. to about 185° C. to providea particle size distribution of the aerosol generated of about 0.1 μm toabout 15 μm.

In some embodiments, the specific temperature range is about 150° C. toabout 175° C. to provide a particle size distribution of the aerosolgenerated of about 0.35 μm to about 0.45 μm. In some embodiments, thespecific temperature range is about 150° C. to about 185° C. to providea particle size distribution of the aerosol generated of about 0.35 μmto about 0.45 μm. In some embodiments, the specific temperature range isabout 150° C. to about 175° C. to provide a particle size distributionof the aerosol generated of about 0.4 μm. In some embodiments, thespecific temperature range is about 150° C. to about 185° C. to providea particle size distribution of the aerosol generated of about 0.4 μm.In some embodiments, the specific temperature range is about 150° C. toabout 175° C. to provide a particle size distribution of the aerosolgenerated of about 0.3 μm to about 5 μm. In some embodiments, thespecific temperature range is about 150° C. to about 185° C. to providea particle size distribution of the aerosol generated of about 0.3 μm.to about 5 μm.

In an embodiment, the particle size of the aerosol generated by theinhalable medicament delivery device, as described herein, is greaterthan about 0.1 μm. In some embodiments, the particle size of the aerosolgenerated is about 0.1 μm to about 10 μm. In some embodiments, theparticle size of the aerosol generated is about 0.1 μm to about 15 μm.In some embodiments, the particle size of the aerosol generated is about0.5 μm to about 10 μm. In some embodiments, the particle size of theaerosol generated is about 0.4 μm. In some embodiments, the particlesize of the aerosol generated is about 0.1 μm, about 0.2 μm, about 0.3μm, about 0.4 μm, about 0.5 μm, about 0.6 μm, about 0.7 μm, about 0.8μm, about 0.9 μm, about 1.0 μm, about 1.5 μm, about 2.0 μm, about 2.5μm, about 3.0 μm, about 3.5 μm, about 4.0 μm, about 4.5 μm, about 5.0μm, about 5.5 μm, about 6.0 μm, about 6.5 μm, about 7.0 μm, about 7.5μm, about 8.0 μm, about 8.5 μm, about 9.0 μm, about 9.5 μm, about 10.0μm, about 10.5 μm, and about 11.0 μm.

In some embodiments, greater than 50% of the particles delivered have aparticle size of about 0.4 μm. In some embodiments, greater than 60% ofthe particles delivered have a particle size of about 0.4 μm. In someembodiments, greater than 70% of the particles delivered have a particlesize of about 0.4 μm. In some embodiments, greater than 80% of theparticles delivered have a particle size of about 0.4 μm. In someembodiments, greater than 90% of the particles delivered have a particlesize of about 0.4 μm.

Provided herein is a method of delivering an inhaled medicament to asubject, comprising generating an aerosol from the inhaled medicamentand heating an aerosol at specific temperature range of about 140° C. toabout 200° C. to provide a Mass Median Aerodynamic Diameter (MMAD) ofthe aerosol generated of about 0.1 μm to about 15 μm, wherein theaerosol is delivered to a specific target site of the subject.

Also provided herein is a method of delivering an inhaled medicament toa subject for the treatment of nicotine replacement therapy comprisinggenerating an aerosol from the inhaled medicament and heating an aerosolat specific temperature range of about 140° C. to about 200° C. toprovide a Mass Median Aerodynamic Diameter (MMAD) of the aerosolgenerated of about 0.1 μm to about 15 μm, wherein the aerosol isdelivered to a specific target site of the subject.

In some embodiments, the specific temperature range is about 150° C. toabout 175° C. to provide a Mass Median Aerodynamic Diameter (MMAD) ofthe aerosol generated of about 0.1 μm to about 15 μm. In someembodiments, the specific temperature range is about 150° C. to about185° C. to provide a particle size distribution of the aerosol generatedof about 0.1 μm to about 15 μm.

In some embodiments, the specific temperature range is about 150° C. toabout 175° C. to provide a Mass Median Aerodynamic Diameter (MMAD) ofthe aerosol generated of about 0.35 μm to about 0.45 μm. In someembodiments, the specific temperature range is about 150° C. to about185° C. to provide a Mass Median Aerodynamic Diameter (MMAD) of theaerosol generated of about 0.35 μm to about 0.45 μm. In someembodiments, the specific temperature range is about 150° C. to about175° C. to provide a Mass Median Aerodynamic Diameter (MMAD) of theaerosol generated of about 0.4 μm. In some embodiments, the specifictemperature range is about 150° C. to about 185° C. to provide a MassMedian Aerodynamic Diameter (MMAD) of the aerosol generated of about 0.4μm. In some embodiments, the specific temperature range is about 150° C.to about 175° C. to provide a Mass Median Aerodynamic Diameter (MMAD) ofthe aerosol generated of about 0.3 μm to about 5 μm. In someembodiments, the specific temperature range is about 150° C. to about185° C. to provide a Mass Median Aerodynamic Diameter (MMAD) of theaerosol generated of about 0.3 μm to about 5 μm.

In an embodiment, the Mass Median Aerodynamic Diameter (MMAD) of theaerosol generated by the inhalable medicament delivery device, asdescribed herein, is greater than about 0.1 μm. In some embodiments, theMass Median Aerodynamic Diameter (MMAD) of the aerosol generated isabout 0.1 μm to about 10 μm. In some embodiments, the Mass MedianAerodynamic Diameter (MMAD) of the aerosol generated is about 0.1 μm toabout 15 μm. In some embodiments, the Mass Median Aerodynamic Diameter(MMAD) is about 0.5 μm to about 10 μm. In some embodiments, the MassMedian Aerodynamic Diameter (MMAD) of the aerosol generated is about 0.4μm. In some embodiments, the a Mass Median Aerodynamic Diameter (MMAD)of the aerosol generated is about 0.1 μm, about 0.2 μm, about 0.3 μm,about 0.4 μm, about 0.5 μm, about 0.6 μm, about 0.7 μm, about 0.8 μm,about 0.9 μm, about 1.0 μm, about 1.5 μm, about 2.0 μm, about 2.5 μm,about 3.0 μm, about 3.5 μm, about 4.0 μm, about 4.5 μm, about 5.0 μm,about 5.5 μm, about 6.0 μm, about 6.5 μm, about 7.0 μm, about 7.5 μm,about 8.0 μm, about 8.5 μm, about 9.0 μm, about 9.5 μm, about 10.0 μm,about 10.5 μm, or about 11.0 μm.

Medicaments

In a variation, the device generates an aerosol comprising an inhalablemedicament. An aerosol may comprise a colloidal suspension of particlesor liquid droplets suspended in for example a liquid or gas. Amedicament may comprise any substance used to treat a subject. Amedicament may, for example, comprise a pharmaceutical, a biologicalagent, or any other therapeutic compound. An inhalable medicament maycomprise a formulation that is inhaled by a subject for the purpose oftreating a medical condition or symptom. An inhalable medicament maycomprise a formulation that is inhaled by a subject for the purpose ofsmoking cessation or nicotine replacement therapy. A subject capable ofusing the described device may comprise a human or animal.

Nicotine Replacement Therapy

The medicament may comprise, for example, nicotine for use in, forexample, nicotine replacement therapy.

Anxiolytics

The medicament may comprise, for example, an anxiolytic. Non-limitingexamples of anxiolytics suitable for delivery with the device describedherein comprise alprazolam, bromazepam, chlordiazepoxide, clonazepam,clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, andtriazolam.

Non-Opioids

The medicament may comprise, for example, a non-opioid based painmedication. Non-limiting examples of non-opioid based pain medicationssuitable for delivery with the device described herein compriseacetylsalicylic acid, acetaminophen, and ketorolac tromethamine.

Opioids

Opioids may, for example, be delivered by the inhalable medicamentdelivery device described herein with similar or improvedbioavailability. Non-limiting examples of opioids suitable for deliverywith the described device include Fentanyl/Fentanyl citrate, Morphinesulfate (MS Contin), Codeine, Tramadol (Ultram), Meperidine (Demerol),Hydromorphone (Dilaudid), Methadone (Dolophine), Oxycodone (Roxicodone),Oxycodone/Acetaminophen (Percocet), Oxycodone/Aspirin (Percodan),Hydrocodone/Acetaminophen (Lortab, Norco, Hycet), andTramadol/Acetaminophen (Ultracet). The bioavailabilities of Codeine,Methadone (Dolophine), Oxycodone (Roxicodone), Oxycodone/Acetaminophen(Percocet), Oxycodone/Aspirin (Percodan), Hydrocodone/Acetaminophen(Lortab, Norco, Hycet), and Tramadol/Acetaminophen (Ultracet) aresimilar when administered PO, and when administered with the inhalablemedicament delivery device described herein. The bioavailability ofFentanyl/Fentanyl citrate is typically around 47-71% when administeredPO, and when delivered as an inhalable medicament with the devicedescribed herein, the bioavailability is greater than 47%. Thebioavailability of Morphine sulfate (MS Contin) is typically around20-40% when administered PO, and when delivered as an inhalablemedicament with the device described herein, the bioavailability isgreater than 40%. The bioavailability of Tramadol (Ultram) is typicallyaround 75-95% when administered PO, and when delivered as an inhalablemedicament with the device described herein, the bioavailability isgreater than 75%. The bioavailability of Meperidine (Demerol) istypically around 57% when administered IM, and when delivered as aninhalable medicament with the device described herein, thebioavailability is greater than 57%. The bioavailability ofHydromorphone (Dilaudid) is typically around 24% when administered PO,and when delivered as an inhalable medicament with the device describedherein, the bioavailability is greater than 24%.

Cannabinoids

Cannabinoids may, for example, be delivered by the inhalable medicamentdelivery device described herein with similar or improvedbioavailability. Non-limiting examples of cannabinoids suitable fordelivery with the described device include tetrahydrocannabinol (THC),as well as synthetic cannabinoids including the 1,5-diarylpyrazoles,quinolines, arylsulfonamides, and eicosanoids related to theendocannabinoids.

Bronchodilators

The medicament may comprise, for example, a bronchodilator. Non-limitingexamples of bronchodilators suitable for delivery with the devicedescribed herein comprise salbutamol/albuterol,levosalbutamol/levalbuterol, pirbuterol, epinephrine, ephedrine,terbutalin, salmeterol, clenbuterol, formoterol, bambuterol, andindacaterol. The medicament may comprise, for example, a steroid.Non-limiting examples of bronchodilators suitable for delivery with thedevice described herein comprise beclomethasone dipropionate,budesonide, flunisolide, fluticasone propionate, mometasone furoate, andtriamcinolone acetonide.

Vasodilators

The medicament may comprise a vasodilator, which may be used to treat avariety of conditions, including without limitation, erectiledysfunction. Such a medicament may comprise a phosphodiesterase (PDE)inhibitor or a prostoglandin. Some non-limiting examples ofphosphodiesterase (PDE) inhibitors that may be delivered using a deviceaccording to this disclosure include Sildenafil (VIAGRA®), Tadalafil(ADCIRCA®, CIALIS®), Vardenafil (LEVITRA®, STAXYN®), and Avanafil(STENDRA®). Prostoglandins that may be delivered with a device accordingto this disclosure include, but are not limited to Alprostadil(CAVERJECT®, MUSE®, EDEX®).

Biologics

The medicament may comprise a biological therapeutic. Non-limitingexamples of biological therapeutics suitable for delivery with thedevice described herein may, for example, comprise DNA, RNA, andproteins. Biologics may be delivered using viral vectors and similarthat would be suitable for use in the formulation. The fluid may furthercomprise an excipient.

Biosimilars

The medicament may comprise a biosimilar therapeutic. Non-limitingexamples of biosimilar therapeutics suitable for delivery with thedevice described herein may, for example, comprise insulin, human growthhormone, various interferons, erythropoietin, and various monoclonalantibodies.

Antivirals

Antivirals may, for example, be delivered by the inhalable medicamentdelivery device described herein with similar or improvedbioavailability. Non-limiting examples of antivirals suitable fordelivery with the described device include Oseltamivir (Tamiflu),Zanamivir (Relenza), Amantadine (Symmetrel), and Rimantidine(Flumadine). The bioavailability of Oseltamivir (Tamiflu) is typicallyaround 75% when administered PO, and when delivered as an inhalablemedicament with the device described herein, the bioavailability isgreater than 75%. The bioavailability of Zanamivir (Relenza) istypically around 4-17%, and when delivered as an inhalable medicamentwith the device described herein the bioavailability is equal to orgreater than 4-17%. The bioavailability of Amantadine (Symmetrel) istypically around 86% when administered PO, and when delivered as aninhalable medicament with the device described herein, thebioavailability is greater than 90%.

Analgesics/Antihistamines

Combination analgesic/antihistamines may, for example, be delivered bythe inhalable medicament delivery device described herein with similaror improved bioavailability. Non-limiting examples of antiviralssuitable for delivery with the described device includeAcetaminophen/Diphenhydramine (Tylenol PM) and Ibuprofen/Diphenhydramine(Advil PM). The bioavailability of Acetaminophen/Diphenhydramine(Tylenol PM) is typically around 65-100% when administered PO, and whendelivered as an inhalable medicament with the device described herein,the bioavailability is around 100%. The bioavailability ofIbuprofen/Diphenhydramine (Advil PM) is typically around 65-100% whenadministered PO, and when delivered as an inhalable medicament with thedevice described herein, the bioavailability is around 100%.

Antitussives

Antitussives may, for example, be delivered by the inhalable medicamentdelivery device described herein with similar or improvedbioavailability. Non-limiting examples of antitussives suitable fordelivery with the described device include Dextromethorphan (Delsym),and Benzocaine/menthol or dextromethorphan. The bioavailability ofDextromethorphan (Delsym), and Benzocaine/menthol or dextromethorphanare similar when administered PO and when administered with theinhalable medicament delivery device described herein.

Decongestants

Decongestants may, for example, be delivered by the inhalable medicamentdelivery device described herein with similar or improvedbioavailability. Non-limiting examples of decongestants suitable fordelivery with the described device include Pseudoephedrine (Sudafed) andPhenylephrine. The bioavailability of Phenylephrine is typically around38% when administered PO, and when delivered as an inhalable medicamentwith the device described herein, the bioavailability is greater than38%.

Antihistamines

Antihistamines may, for example, be delivered by the inhalablemedicament delivery device described herein with similar or improvedbioavailability. Non-limiting examples of antihistamines suitable fordelivery with the described device include Diphenhydramine (Benadryl),Hydroxyzine (Atarax), Cetirizine (Zyrtec), Loratadine (Claritin), andFexofenadine (Allegra). The bioavailability of Diphenhydramine(Benadryl) is typically around 65-100% when administered PO, and whendelivered as an inhalable medicament with the device described herein,the bioavailability is greater than 65%. The bioavailability ofCetirizine (Zyrtec) is typically around 70% when administered PO, andwhen delivered as an inhalable medicament with the device describedherein, the bioavailability is greater than 70%. The bioavailabilitiesof Hydroxyzine (Atarax), Loratadine (Claritin), and Fexofenadine(Allegra) are similar when administered PO and when administered withthe inhalable medicament delivery device described herein.

Expectorants

Expectorants may, for example, be delivered by the inhalable medicamentdelivery device described herein with similar or improvedbioavailability. Non-limiting examples of expectorants suitable fordelivery with the described device include Guaifenasin (Mucinex). Thebioavailability of Guaifenasin (Mucinex) is similar when administered POand when administered with the inhalable medicament delivery devicedescribed herein.

Nasal Sprays

Nasal sprays may, for example, be delivered by the inhalable medicamentdelivery device described herein with similar or improvedbioavailability. Non-limiting examples of nasal sprays suitable fordelivery with the described device include Azelastine (Astelin),Beclomethasone (Beconase, Qnasl), Mometasone (Nasonex), andOxymetazoline (Afrin). The bioavailability of Azelastine (Astelin) istypically around 40% when administered as a nasal spray, and whendelivered as an inhalable medicament with the device described herein,the bioavailability is greater than 40%. The bioavailability ofBeclomethasone (Beconase, Qnasl) is typically around 41-43% whenadministered as a nasal spray, and when delivered as an inhalablemedicament with the device described herein, the bioavailability isaround 25-60%. The bioavailability of Mometasone (Nasonex) is typicallyaround 1% when administered as an inhalable spray, and when delivered asan inhalable medicament with the device described herein, thebioavailability is greater than 1%. The bioavailability of Oxymetazoline(Afrin) is similar when administered PO and when administered with theinhalable medicament delivery device described herein.

Motion Sickness Medications

Motion sickness medications may, for example, be delivered by theinhalable medicament delivery device described herein with similar orimproved bioavailability. Non-limiting examples of motion sicknessmedications suitable for delivery with the described device includeDimenhydrinate (Dramamine), Scopolamine (Transderm), and Meclizine(Bonine). The bioavailabilities of Dimenhydrinate (Dramamine)Scopolamine (Transderm), and Meclizine (Bonine) are similar whenadministered PO and when administered with the inhalable medicamentdelivery device described herein.

Analgesics

Analgesics may, for example, be delivered by the inhalable medicamentdelivery device described herein with similar or improvedbioavailability. Non-limiting examples of analgesics suitable fordelivery with the described device include Phenol (Chloraseptic spray),Menthol (Vicks VapoDrops), Duloxetine (Cymbalta), Pregabalin (Lyrica),Ibuprofen (Advil), Butalbital/Acetaminophen/Caffeine (Fioricet),Sumatriptan (Imitrex), Topiramate (Topamax), Carisoprodol (Soma),Tizanidine (Zanaflex), Naproxen sodium (Aleve), Ketorolac (Toradol),Celecoxib (Celebrex), Aspirin (Bayer), Acetaminophen (Tylenol, Ofirmev),and Acetaminophen/Caffeine/Pyrilamine (Midol Complete). Thebioavailabilities of Phenol (Chloraseptic spray), Menthol (VicksVapoDrops), Pregabalin (Lyrica), Butalbital/Acetaminophen/Caffeine(Fioricet), Carisoprodol (Soma), and Acetaminophen/Caffeine/Pyrilamine(Midol Complete) are similar when administered PO, and when administeredwith the inhalable medicament delivery device described herein. Thebioavailability of Duloxetine (Cymbalta) is typically around 30-80% whenadministered PO, and when delivered as an inhalable medicament with thedevice described herein, the bioavailability is greater than 30%. Thebioavailability of Ibuprofen (Advil) is typically around 58-98% whenadministered PO, and when delivered as an inhalable medicament with thedevice described herein, the bioavailability is greater than 58%. Thebioavailability of Sumatriptan (Imitrex) is typically around 25% whenadministered through a nasal spray, and when delivered as an inhalablemedicament with the device described herein, the bioavailability isgreater than 15-25%. The bioavailability of Aspirin (Bayer) is typicallyaround 61-80% when administered PO, and when delivered as an inhalablemedicament with the device described herein, the bioavailability isgreater than 61%. The bioavailability of Acetaminophen (Tylenol,Ofirmev) is typically around 85-100% when administered PO, and whendelivered as an inhalable medicament with the device described herein,the bioavailability is greater than 85%.

Anesthetics

Anesthetics may, for example, be delivered by the inhalable medicamentdelivery device described herein with similar or improvedbioavailability. Non-limiting examples of anesthetics suitable fordelivery with the described device include Neostigmine (Prostigmin),Glycopyrrolate (Glycate), Isoflurane (Forane), Sevoflurane (Ultane),Desflurane (Suprane), Etomidate (Amidate), Propofol (Diprivan),Lidocaine (Xylocaine), Bupivicaine (Marcaine), Rocuronium (Zemuron),Vecuronium (Norcuron), Cisatracurium (Nimbex), Succinylcholine,Dexmedetomidine (Precedex), and Midazolam (Versed). The bioavailabilityof Isoflurane (Forane), Sevoflurane (Ultane), Desflurane (Suprane),Etomidate (Amidate), Propofol (Diprivan), Bupivicaine (Marcaine),Rocuronium (Zemuron), Vecuronium (Norcuron), Cisatracurium (Nimbex),Succinylcholine, and Dexmedetomidine (Precedex) are similar whenadministered PO, and when administered with the inhalable medicamentdelivery device described herein. The bioavailability of Neostigmine(Prostigmin) is typically around 1-2% when administered PO, and whendelivered as an inhalable medicament with the device described herein,the bioavailability is greater than 1%. The bioavailability of Lidocaine(Xylocaine) is typically around 35% when administered PO, and whendelivered as an inhalable medicament with the device described herein,the bioavailability is greater than 35%. The bioavailability ofMidazolam (Versed) is typically around 36% when administered PO, andwhen delivered as an inhalable medicament with the device describedherein, the bioavailability is greater than 36%.

Antimicrobials

Antimicrobials may, for example, be delivered by the inhalablemedicament delivery device described herein with similar or improvedbioavailability. Non-limiting examples of antimicrobials suitable fordelivery with the described device include Gentamicin, Tobramycin(Tobi), Bacitracin (BACiiM), Chlorhexidine (Betasept), Fluconazole(Diflucan), Micafungin (Mycamine), Permethrin (Eimite), Ivermectin(Stromectol), Meropenem (Merrem), Ertapenem (Invanz), Cefazolin (Ancef),Cephalexin (Keflex), Cefoxitin (Mefoxin), Cefuroxime (Zinacef),Ceftriaxone (Rocephin), Ceftazidime (Fortaz), Cefepime (Maxipime),Ceftaroline (Teflaro), Ciprofloxacin (Cipro), Levofloxacin (Levaquin),Vancomycin (Vancocin), Azithromycin (Zithromax), Clarithromycin(Biaxin), Pencillin G, V, Amoxicillin (Amoxil), Amoxicillin/clavulanate(Augmentin), Piperacillin/tazobactam (Zosyn), Nafcillin,Trimethoprim/sulfamethoxazole (Bactrim), Minocycline (Minocin),Tetracycline, Doxycycline (Adoxa), Atovaquone/Proguanil (Malarone),Isoniazid, Rifampin, Ganciclovir (Cytovene), Valganciclovir (Valcyte),Acyclovir (Zovirax), Entecavir (Baraclude), Ribavirin (Copegus,Rebetol), Abacavir (Ziagen), Zidovudine (Retrovir), Efavirenz (Sustiva),Nevirapine (Viramune), Nelfinavir (Viracept), Ritonavir (Norvir), andRaltegravir (Isentress). The bioavailabilities of Bacitracin (BACiiM),Micafungin (Mycamine), Permethrin (Eimite), Ivermectin (Stromectol),Meropenem (Merrem), Cephalexin (Keflex), Cefuroxime (Zinacef),Ceftriaxone (Rocephin), Ceftaroline (Teflaro), Amoxicillin (Amoxil),Amoxicillin/clavulanate (Augmentin), Fluconazole (Diflucan),Tetracycline, Doxycycline (Adoxa), Valganciclovir (Valcyte), Entecavir(Baraclude), Efavirenz (Sustiva), Nelfinavir (Viracept), and Ritonavir(Norvir) are similar when administered PO, and when administered withthe inhalable medicament delivery device described herein. Thebioavailability of Gentamicin is typically negligible when administeredPO and around 100% when administered IV, and when delivered as aninhalable medicament with the device described herein, thebioavailability is greater than 76%. The bioavailability of Tobramycin(Tobi) is typically around 1-16.6% when administered as an inhalable,and when delivered as an inhalable medicament with the device describedherein, the bioavailability is greater than 1%. The bioavailability ofChlorhexidine (Betasept) is typically around 4% when administered PO,and when delivered as an inhalable medicament with the device describedherein, the bioavailability is greater than 4%. The bioavailability ofErtapenem (Invanz) is typically around 90% when administered IV, andwhen delivered as an inhalable medicament with the device describedherein, the bioavailability is greater than 90%. The bioavailability ofCefazolin (Ancef) is typically around 78% when administered IV, and whendelivered as an inhalable medicament with the device described herein,the bioavailability is greater than 78%. The bioavailability ofCefoxitin (Mefoxin) is typically around 7-17% when administered PR, andwhen delivered as an inhalable medicament with the device describedherein, the bioavailability is greater than 7%. The bioavailability ofCefepime (Maxipime) is typically around 82% when administered IM, andwhen delivered as an inhalable medicament with the device describedherein, the bioavailability is greater than 82%. The bioavailability ofCiprofloxacin (Cipro) is typically around 60-80% when administered PO,and when delivered as an inhalable medicament with the device describedherein, the bioavailability is greater than 60%. The bioavailability ofLevofloxacin (Levaquin) is typically around 99% when administered PO,and when delivered as an inhalable medicament with the device describedherein, the bioavailability is greater than 99%. The bioavailability ofVancomycin (Vancocin) is typically negligible when administered PO, andwhen delivered as an inhalable medicament with the device describedherein, the bioavailability is greater than 38%. The bioavailability ofAzithromycin (Zithromax) is typically around 38% when administered PO,and when delivered as an inhalable medicament with the device describedherein, the bioavailability is greater than 38%. The bioavailability ofClarithromycin (Biaxin) is typically around 55% when administered PO,and when delivered as an inhalable medicament with the device describedherein, the bioavailability is greater than 50%. The bioavailability ofPenicillin G, V is typically around 30-80% when administered PO, andwhen delivered as an inhalable medicament with the device describedherein, the bioavailability is greater than 30%. The bioavailability ofPiperacillin/tazobactam (Zosyn) is typically around 71% whenadministered IM, and when delivered as an inhalable medicament with thedevice described herein, the bioavailability is greater than 71%. Thebioavailability of Nafcillin is typically around 50% when administeredPO, and when delivered as an inhalable medicament with the devicedescribed herein, the bioavailability is greater than 50%. Thebioavailability of Trimethoprim/sulfamethoxazole (Bactrim) is typicallyaround 90-100% when administered PO, and when delivered as an inhalablemedicament with the device described herein, the bioavailability isgreater than 90%. The bioavailability of Minocycline (Minocin) istypically around 90% when administered PO, and when delivered as aninhalable medicament with the device described herein, thebioavailability is greater than 90%. The bioavailability ofAtovaquone/Proguanil (Malarone) is typically around 23% whenadministered PO, and when delivered as an inhalable medicament with thedevice described herein, the bioavailability is greater than 23%. Thebioavailability of Isoniazid is typically around 90% when administeredPO, and when delivered as an inhalable medicament with the devicedescribed herein, the bioavailability is greater than 90%. Thebioavailability of Rifampin is typically around 90-95% when administeredPO, and when delivered as an inhalable medicament with the devicedescribed herein, the bioavailability is greater than 90%. Thebioavailability of Ganciclovir (Cytovene) is typically around 5% whenadministered PO, and when delivered as an inhalable medicament with thedevice described herein, the bioavailability is greater than 5%. Thebioavailability of Acyclovir (Zovirax) is typically around 10-20% whenadministered PO, and when delivered as an inhalable medicament with thedevice described herein, the bioavailability is greater than 10%. Thebioavailability of Ribavirin (Copegus, Rebetol) is typically around 64%when administered PO, and when delivered as an inhalable medicament withthe device described herein, the bioavailability is greater than 64%.The bioavailability of Abacavir (Ziagen) is typically around 83% whenadministered PO, and when delivered as an inhalable medicament with thedevice described herein, the bioavailability is greater than 83%. Thebioavailability of Abacavir (Ziagen) is typically around 61-89% whenadministered IV, and when delivered as an inhalable medicament with thedevice described herein, the bioavailability is greater than 61%. Thebioavailability of Nevirapine (Viramune) is typically around 80-94% whenadministered PO, and when delivered as an inhalable medicament with thedevice described herein, the bioavailability is greater than 84%. Thebioavailability of Raltegravir (Isentress) is typically around 20-43%when administered PO, and when delivered as an inhalable medicament withthe device described herein, the bioavailability is greater than 20%.The bioavailability of Raltegravir (Isentress) is typically around20-43% when administered PO, and when delivered as an inhalablemedicament with the device described herein, the bioavailability isgreater than 20%.

Biosimilar Molecules

Biosimilar molecules may, for example, be delivered by the inhalablemedicament delivery device described herein with similar or improvedbioavailability. Non-limiting examples of bisimilar molecules suitablefor delivery with the described device include Interferon alfa 2b(Pegasys), Adenovirus 4, Albumin, human (Plasbumin, AlbuRx, Albutein,Albuminar), Alpha-1-proteinase inhibitor, human (Prolastin, Aralast,Zemaira, Glassia), Anthrax vaccine adsorbed (BioThrax), Antihemophlicfactor, human (Koate, Hemofil, Monoclate), Antihemophlic factor,recombinant (Kogenate, Helixate, Refacto, Novoeight), Antihemophlicfactor, recombinant, Fc fusion protein (Eloctate), Antihemophlic factor,recombinant, plasma/albumin free (Advate, xyntha), Antihemophlic factor,von Willebrand factor complex, human (Alphanate, Humate), Anti-Inhibitorcoagulant complex (Autoplex, Feiba), Antithrombin, recombinant (ATryn),Antithrombin III, human (Thrombate III), Anti-thymocyte globulin, rabbit(Thymoglobulin), Antivenin polyvalent, crotalidae, Antivenin,Lactrodectus mactans, Antivenin, Micrurus Fulvius, Autologous culturedchondrocytes (Carticel), Azficel-T (LaViv), BCG Live (Tice, TheraCys),BCG Vaccine, Botulism antitoxin heptavalent, equine (BAT), Botulismimmune globulin intravenous, human (Baby BIG), C1 esterase inhibitor,human (Cinryze, Berinert), C1 esterase inhibitor, recombinant(Ruconest), Candida albicans skin test antigen (Candin), Centruroides(scorpion) immune F (ab′)2 (equine) injection (Anascorp), Coagulationfactor IX, human (AlphaNine, Mononine), Coagulation factor IX,recombinant (BeneFIX, RIXUBIS), Coagulation factor IX, recombinant, Fcfusion protein (Alprolix), Coagulation factor VIIa, recombinant(NovoSeven), Coagulation factor XIII A subunit, recombinant (Tretten),Coccidioides immitis spherule-derived skin test antigen (Spherusol),Crotalidae polyvalent immune fab, ovine (CroFab), CMV immune globulinintravenous, human (CytoGam), Digoxin immune fab, ovine (Digibind,digiFab), DTaP toxoids adsorbed (Infanrix, Daptacel, Tripedia), DTaPtoxoids adsorbed and inactivated poliovirus vaccine (Kinrix),DTaP/Hepatitis B (recombinant) and inactivated poliovirus vaccine(Pediarix), Factor IX complex (Profilnine, Bebulin), Factor XIIIconcentrate, human (Corifact), Fibrin sealant, human (Crosseal, Evicel,Artiss), Fibrin sealant (Tisseel), Fibrin sealant patch (TachoSil,Evarrest), Fibrinogen concentrate, human (RiaSTAP), Haemophilus Bconjugate (meningococcal protein)/Hep B (recombinant) vaccine (COMVAX),Haemophilus B conjugate, meningococcal protein (PedvaxHlB), HaemophilusB conjugate vaccine, tetanus toxoid (ActHIB, OmniHIB, Hiberix),Haemophilus B conjugate vaccine, tetanus toxoid, reconstituted with DTaPtoxoids (Pentacel), Hematopoietic progenitor cells, cord:HPC-C(Hemacord), Hemin for injection (Panhematin), Hepatitis Ainactived/Hep B recombinant vaccine (Twinrix), Hepatitis A inactived(Havrix/VAQTA), Hepatitis B IG, human (BayHep, HyperHep, Nabi-HB,HepaGam B), Hepatitis B IG intravenous, human (HepaGam BT), Hepatitis Bvaccine, recombinant (Recombivax/HB), Engerix-B), HPC, cord blood(DuCord, Allocord), HPV bivalent (16/18) vaccine, recombinant(Cervarix), HPV quad (6/11/16.18) vaccine, recombinant (Gardisil),Immune globulin, human (Gammastan, BayGam, IG infusion, human (Polygam,Kiovig, Gammagard, IG injection, human 10% caprylate/chromatographypurified (Gamunex-C, Gammaked), IG intravenous, human (Sandoglobulin,Gammagard, Octagam, Flebogamma, Bivigam), IG intravenous, human 10%liquid (Privigen), IG intravenous, human 5% liquid (Gammaplex), IG SQ,human 20% liquid (Hizentra), Influenza A (H5N1) virus monovalentvaccine, adjuvanted, Influenza vaccine (FluBlok, Agriflu), Influenzavaccine live, intranasal (FluMist), Influenza virus vaccine (FluVirin,Fluzone, Fluarix, FluLaval, Afluria, Flucelvax), Influenza virusvaccine, H5N1, Insects (whole body), mite dermatophagoides farinae,Insects (whole body), mite dermatophagoides pteronyssinus, Japaneseencephalitis vaccine, inactivated, adsorbed (Ixiaro), Lymphocyte IG,anti-thymocyte globulin, equine (Atgam), MMR virus vaccine live (M-M-RII), MMR and VZV vaccine live (ProQuad), Meningococcal (A/C/Y/W-135)oligosaccharide diphtheria CRM197 conjugate vaccine (Menveo),Meningococcal (A/C/Y/W-135) polysaccharide diphtheria CRM197 conjugatevaccine (Menactra), Meningococcal (C/Y) and Haemophilus B tetanus toxoidconjugate vaccine (Menhibrix), Meningococcal polysaccharide vaccine,group A (Menomune-A), Meningococcal polysaccharide vaccine, group C(Menomune-C), Meningococcal polysaccharide vaccine, groups A/C combined(Menomune-A/C), Meningococcal polysaccharide vaccine, groups A/C/Y/W-135combined (Menomune), Allergen patch test kit, Non-standardizedallergenics, Normal horse serum, Plague vaccine, Plasma proteinfraction, human (plasmanate, protenate), Penumococcal 13-valentconjugate vaccine, Dipththeria CRM197 protein (Prevnar 13), Pneumococcal7-valent conjugate vaccine, Dipththeria CRM197 protein (Prevnar),Pneumococcal vaccine, polyvalent (Pneumovax 23), Poliovirus inactivated(IPOL), Poliovirus inactivated, human diploid cell (Poliovax),Pollens—grasses, bermuda grass cynodon dactylon, Pollens—grasses,bluegrass, kentucky (June) poa pratensis, Pollens—grasses, fescue,meadow festuca elatior, Pollens—grasses, orchard grass Dactylisglomerata, Pollens—grasses, redtop agrostis alba, Pollens—grasses,ryegrass, perennial Lolium perenne, Pollens—grasses, sweet vernal grassanthoxanthum odoratum, Pollens—grasses, timothy phleum pratense,Pollens—weeds and garden plants, ragweed, short Ambrosia artemisiifolia,Pollens—weeds and garden plants, ragweed, short ambrosia eliator, Pooledplasma (human), solvent/detergent treated (Octaplas), Positive skin testcontrol—histamine (Histatrol), Protein C concentrate, human (Ceprotin),Prothrombin complex concentrate, human (Kcentra), Rabies vaccine(RabAvert), Rabies IG, human (BayRab, HyperRab, Imogam), Rabies vaccineadsorbed (BioRab), Rho(D) IG, human (BayRho-D, RhoGam), Rho(D) IG, humanintravenous (WinRho SDF, Rhophylac), Rotavirus vaccine, live, oral(Rotarix), Rotavirus vaccine, live, oral, pentavalent (RotaTeq), Shortragweed extract (Ragwitek), Sipuleucel-T (Provenge), Smallpox (vaccinia)vaccine, live (ACAM2000), Sweet vernal, orchard, perennial rye, timothyand kentucky blue grass mixed pollens allergen extract (Oralair), TDapadsorbed (Tenivac, Decavac), Tetatuns IG, human (BayTet), Tetanus toxoidadsorbed, Tetanus toxoid, reduced diphtheria toxoid and acellularpertussis vaccine, adsorbed (Boostrix, Adacel), Timothy grass pollenallergen extract (Grastek), Tuberculin, purified protein derivative(Aplisol, Tubersol), Typhoid vaccine live oral Ty21a (Vivotif), TyphoidVi polysaccharide vaccine (Typhim Vi), Vaccinia IG Intravenous, human(CNJ-016), Varicella virus vaccine, live (Varivax), VZV IG, human(VariZIG), Venoms, honey bee venom (Pharmalgen), Venoms, wasp venomprotein, Venoms, white faced hornet venom protein, Venoms, yellow hornetvenom protein, Venoms, yellow jacet venom protein, von Willebrandfactor/coagulation F VIII complex, human (Wilate), Yellow fever vaccine(YF-Vax), Zoster vaccine live (Zostavax), Abatacept (Orencia), Abciximab(ReoPro), AbobotulinumtoxinA (Dysport), Adalimumab (Humira),Ado-trastuzumab ematansine (Kadcyla), Afibercept (Eylea), Agalsidasebeta (Fabrazyme), Albiglutide (Tanzeum), Aldesleukin (Proleukin),Alefacept (Amevive), and Alemtuzumab. The bioavailabilities ofAdenovirus 4, Albumin, human (Plasbumin, AlbuRx, Albutein, Albuminar),Alpha-1-proteinase inhibitor, human (Prolastin, Aralast, Zemaira,Glassia), Anthrax vaccine adsorbed (BioThrax), Antihemophlic factor, andAnti-Inhibitor coagulant complex (Autoplex, Feiba) are similar whenadministered PO and when administered with the inhalable medicamentdelivery device described herein. The bioavailability of Interferon alfa2b is typically around 80-90% when administered IM, and when deliveredas an inhalable medicament with the device described herein, thebioavailability is greater than 80%. In general, the disclosed deliverywill be improved when compared to other delivery methods except forintravenous injection, which is by definition 100% BA.

Additives

In an embodiment, a medicament comprises an excipient that, for example,increases the volume of the medicament. An excipient may also, forexample, aid in the effective delivery of the medicament to a target.

In an embodiment, the medicament is stored as a liquid formulation. Thisliquid formulation of the medicament may be comprised primarily ofglycerol acting as an excipient. The medicament may be pressurized bythe use of carbon dioxide. For example, the medicament may be composedof a miscible solution of carbon dioxide and glycerol.

Glycerol has numerous advantageous properties. Glycerol is deemed safefor human inhalation. Glycerol has bacteriostatic properties. Glycerolmay facilitate delivery of fragile biological therapeutics. Otherprimary liquid formulation components are also possible—such as waterbased or propylene glycol based. The medicament may also comprise otherliquids similar to glycerol that are suitable for inhalation inaerosolized or vaporized form—such as sugar alcohols or diols. Thehygroscopic properties of glycerol may be used to control for particlegrowth as the aerosol travels through the airways. The hygroscopicnature of glycerol is such that the MMAD of the particle will increaseas the particle uptakes water in the humid human airway. This propertyis important as the initially generated aerosol can be biased to besmall enough to mitigate losses through impaction, but evolve throughhygroscopic enlargement to reach the target size for alveolar deliveryof the excipient.

Examples of suitable excipients other than glycerol include, but are notlimited to, the following: alcohols and polyols, such as ethanol,isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol,butanediols and isomers thereof, pentaerythritol, sorbitol, mannitol,transcutol, dimethyl isosorbide, polyethylene glycol, polypropyleneglycol, polyvinylalcohol, hydroxypropyl methylcellulose and othercellulose derivatives, cyclodextrins and cyclodextrin derivatives;ethers of polyethylene glycols having an average molecular weight ofabout 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether(glycofurol) or methoxy PEG; amides and other nitrogen-containingcompounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam,N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone,N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esterssuch as ethyl propionate, tributylcitrate, acetyl triethylcitrate,acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate,ethyl butyrate, triacetin, propylene glycol monoacetate, propyleneglycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactoneand isomers thereof, β-butyrolactone and isomers thereof; and othersolubilizers known in the art, such as dimethyl acetamide, dimethylisosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycolmonoethyl ether, and water.

An acid, such as ascorbic acid, may be employed to acidify themedicament (e.g., to a low pH of around 4-5 in order to mitigate andreduce the absorption of the liquid formulation through the skin(transdermal absorption). Acidifying the medicament can also be used tomitigate or otherwise reduce the mucosal absorption of the medicamentmixture. The acidification may be achieved by using other acids as well.The acidification of the medicament may also help decrease the risk ofexposure to the unintended exposure to the active ingredients of themedicament by reducing transdermal and or mucosal absorption.Acidification may also, for example, pH buffer the basic pulmonarytissue, facilitating efficient diffusion of the medicament. In addition,the acidification of the medicament may serve as a deterrent toinjection of the active ingredients of the medicament as a form of abuseof one or more active ingredients of the medicament. Acidification usingascorbic or citric acid (or others) may be used to increase trachealstimulation, such as would be desirable when replicating the sensorycues and organoleptic experience of smoking a tobacco cigarette or othercombustible material.

In some embodiments, the formulation comprises the medicament andascorbic acid. In some embodiments, the amount of ascorbic acid providesthe formulation a pH of about 4 to about 5. In some embodiments, theamount of ascorbic acid is X % by weight of ascorbic acid.

In some embodiments, an organosulfur compound is used to increase theabsorption and diffusion of the medicament. For a non-limiting example,the organosulfur compound is dimethyl sulfoxide (DMSO). In someembodiments the formulation comprises the medicament and an organosulfurcompound. The formulation may comprise at most 5% by weight oforganosulfur compound. The formulation may comprise at most 5% byweight, about 5% by weight, 0.01% to 5% by weight, about 0.01% to about5%, 0.05% to 5% by weight, about 0.05% to about 5%, 0.05% to 4% byweight, about 0.05% to about 4%, 0.01% to 3% by weight, about 0.01% toabout 3%, 0.01% to 2% by weight, about 0.01% to about 2%, about 1%,about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about0.7%, about 0.8%, or about 0.9% by weight of organosulfur compound. Theformulation may comprise at most 5% by weight of dimethyl sulfoxide(DMSO). The formulation may comprise at most 5% by weight, about 5% byweight, 0.01% to 5% by weight, about 0.01% to about 5%, 0.05% to 5% byweight, about 0.05% to about 5%, 0.05% to 4% by weight, about 0.05% toabout 4%, 0.01% to 3% by weight, about 0.01% to about 3%, 0.01% to 2% byweight, about 0.01% to about 2%, about 1%, about 1.5%, about 2%, about2.5%, about 3%, about 3.5%, about 4%, about 0.1%, about 0.2%, about0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, orabout 0.9% by weight of dimethyl sulfoxide (DMSO).

Excipients may also be used to enhance the drug formulation or theperformance of the claimed device. For example, excipients include butare not limited to surfactants, preservatives, flavorings, antioxidants,antiaggregating agents, and cosolvents. In some embodiments, themedicament is flavored with an orange or bubble gum flavor to make themedicament more palatable, especially for young children.

Propellants

The medicament may further comprise a propellant in some embodiments.Examples of suitable propellants include but are not limited to inertgases, mixtures of inert gases, chlorofluorocarbons (CFCs), andhydrofluoroalkanes (HFAs). Examples of suitable inert gases include butare not limited to carbon dioxide and nitrogen. Other examples ofsuitable propellants include CFC-11 (CCl₃F), CFC-12 (CCl₂F₂), CFC-14(CCl₂F₄), HFA-134a (C₂H₂F₄), HFA-227 (C₃HF₇), HCFC-22(difluorochloromethane), and HFA-152 (difluroethane and isobutane).

In some embodiments, the propellant is an inert gas. In someembodiments, the propellant is carbon dioxide. In some embodiments, thepropellant is nitrogen. In some embodiments, the propellant is achlorofluorocarbon. In some embodiments, the propellant is ahydrofluoroalkane.

Methods of Treatment

Targeted Areas

In one aspect, the device may generate particles suitable for depositionin the mouth (e.g., for taste). In another example, the device maygenerate particles suitable for deposition in the pulmonary region for afast acting effect. The location of deposition of aerosol particleswithin the respiratory system strongly determines the effectiveness ofthe administration of the medicament.

In another aspect, larger droplets or larger particles can be deliveredto the trachea to, for example, promote tracheal stimulation. Trachealstimulation may create a pleasant sensation in a subject. For example,when the device described herein delivers nicotine as a NicotineReplacement Therapy (NRT), delivery of a droplet that causes trachealstimulation may be a pleasant stimulation for a subject that, forexample, promotes continued use of the therapy. Tracheal stimulation mayalso mimic the tracheal stimulation that some smokers experience.

In another aspect, a vapor may be useful for the delivery oforganoleptic or sensory stimulating factors such as flavor.

The target of the medicament delivery may, for example, comprise thelung or a specific portion or area of the lung. The target of themedicament delivery may, for example, comprise the systemic vasculature.As will be further described herein, a target of medicament delivery,and a dose of medicament delivered to the target may be controlled by,for example, controlling the aerosol composition. That is, bycontrolling, for example, the droplet size, droplet shape, or the degreeof vaporization. In addition, multiple lung targets may be targeted withthe same medicament delivery. In an embodiment, a single aerosol mixtureof different sized particles is generated. In an embodiment, two or moreaerosols comprising different particle sizes are generated and deliveredconsecutively to the subject. In an embodiment, an aerosol particle sizeis modulated over time using the methods, devices and systems describedherein. In these three embodiments of a single aerosol mixturecontaining different sized particles and of a plurality of aerosolcompositions comprising different particle sizes, larger particles willtend to travel to the upper airway and smaller particles in the aerosolmixture will tend to travel deeper into the lung. In these embodiments,the inhalable medicament delivery device may be, for example, used todeliver a numbing agent comprising of larger aerosol particles togetherwith a medicament comprising smaller particles. The numbing agent willbe expected to numb the oropharynx so that there is less resistance tothe smaller sized medicament intended to travel further along theairway, thus, improving the efficacy of delivery of the medicament. Inan embodiment, three different sized particles are delivered so thateach particle targets a different part of the airway. For example, aflavorant particle size may comprise a particle size equal to, forexample, about 15 μm, a numbing agent particle size may comprise aparticle size equal to, for example, about 10 μm, and particle size maycomprise a particle size equal to about 15 μm, and a medicament particlesize may comprise a particle size equal to, for example, about 5 μm.

The lungs comprise the alveoli, and pulmonary airways including thetrachea, bronchi, and bronchioles. The human right lung comprises threelobes, the right superior lobe, middle lobe, and right inferior lobe.The human left lung comprises the left superior lobe, the lingula of thesuperior lobe, and left inferior lobe. The respective human lung lobesare generally positioned superiorly to inferiorly in a human standing orsitting in an upright position. The target of the inhalable medicamentmay for example comprise the superior portion of the lung, for example,comprising the right superior and left superior lobes. Such targeteddelivery within the lung may be advantageous, for example, for targeteddelivery of a chemotherapeutic agent to a localized lung lesion. Suchtargeted delivery within the lung may be advantageous, for example, fordelivery of an antimicrobial agent to a localized infectious lesionwithin the lung. Numerous other advantageous examples of targetedpulmonary medicament delivery exist and will be understood by thosehaving skill in the art.

Delivery of medicament to the lungs can also provide a means of rapiddelivery of a medicament into the bloodstream through absorption intothe alveolar-capillary membrane and the pulmonary vasculature, comprisedof pulmonary arteries and veins. Generally, the pulmonary veins returnoxygenated blood from the pulmonary circulation to the left atrium ofthe heart, wherein the blood travels to the left ventricle of the heartand then into systemic circulation, wherein the blood travels throughthe various tissue of the body. An aerosolized medicament that iscapable of crossing the pulmonary blood barrier may enter the pulmonarycirculation, travel through a pulmonary vein to the heart, and then intothe systemic circulation, so that the medicament can be delivered totissue in the body beyond the lungs. Systemic delivery of medicamentthrough the pulmonary vasculature system may offer an advantageousalternative to, for example, to intravenous delivery of medicament.

In some embodiments, the aerosol generated is deposited in the mouth ofthe subject. In further embodiments, the particles of aerosol generatedhas a particle size of about 0.1 μm to about 15 μm or a MMAD of about0.1 to about 15 μm. In some embodiments, the aerosol generated isdeposited in the trachea of the subject. In further embodiments, theparticles of aerosol generated has a particle size of about 0.1 μm toabout 15 μm or a MMAD of about 0.1 to about 15 μm. In some embodiments,the aerosol generated is deposited in the lung of the subject. Infurther embodiments, the particles of aerosol generated has a particlesize of about 0.1 μm to about 15 μm or a MMAD of about 0.1 to about 15μm. In some embodiments, the aerosol generated is deposited in thesuperior lung lobe of the subject. In further embodiments, the particlesof aerosol generated has a particle size of about 0.1 μm to about 15 μmor a MMAD of about 0.1 to about 15 μm. In some embodiments, the aerosolgenerated is deposited in the middle lung lobe of the subject. Infurther embodiments, the particles of aerosol generated has a particlesize of about 0.1 μm to about 15 μm or a MMAD of about 0.1 to about 15μm. In some embodiments, the aerosol generated is deposited in theinferior lung lobe of the subject. In further embodiments, the particlesof aerosol generated has a particle size of about 0.1 μm to about 15 μmor a MMAD of about 0.1 to about 15 μm.

In some embodiments, the aerosol generated is deposited in theoropharynx. In further embodiments, the particles of aerosol generatedhas a particle size of about 0.1 μm to about 15 μm or a MMAD of about0.1 to about 15 μm. In some embodiments, the aerosol generated isdeposited in the central airways. In further embodiments, the particlesof aerosol generated has a particle size of about 0.1 μm to about 15 μmor a MMAD of about 0.1 to about 15 μm. In some embodiments, the aerosolgenerated is deposited in the small airways. In further embodiments, theparticles of aerosol generated has a particle size of about 0.1 μm toabout 15 μm or a MMAD of about 0.1 to about 15 μm. In some embodiments,the aerosol generated is deposited in the alveoli. In furtherembodiments, the particles of aerosol generated has a particle size ofabout 0.1 μm to about 15 μm or a MMAD of about 0.1 to about 15 μm. Insome embodiments, the aerosol generated is delivered to the pulmonaryvasculature of the subject. In further embodiments, the particles ofaerosol generated has a particle size of about 0.1 μm to about 15 μm ora MMAD of about 0.1 to about 15 μm.

The foregoing description of the invention has been presented forpurposes of illustration and description. It is not intended to beexhaustive or to limit the invention to the precise form disclosed, andother modifications and variations may be possible in light of the aboveteachings. The embodiment was chosen and described in order to bestexplain the principles of the invention and its practical application tothereby enable others skilled in the art to best utilize the inventionin various embodiments and various modifications as are suited to theparticular use contemplated. It is intended that the appended claims beconstrued to include other alternative embodiments of the inventionexcept insofar as limited by the prior art.

EXAMPLES

The following examples are provided for illustrative purposes only andnot to limit the scope of the claims provided herein.

Example 1

Using any one of the devices described in this present application, theparticle size distribution of the aerosol generated as was measured as afunction of the temperature at which the aerosol is heated at. The massmedian aerodynamic diameter (MMAD) was measured by using a SpraytecParticle Size Analyzer and a thermally regulated aerosol generator. Inthe following examples, pressure: 10%=about 8 psi, 50%=about 40-50 psi,100%=about 80-90 psi of pressure applied to the device. Glycerol with avariable % of water was used the test liquid medicament. Results areshown in Tables 1 to 4.

TABLE 1 Mass Median Aerodynamic Diameter (MMAD) of Glycerol with 0.5%Water Temperature MMAD (° C.) Pressure (μm) 100 10% 0.44 100 50% 0.49100 100%  0.87 150 10% 1.67 150 50% 0.50 150 100%  0.44 175 10% 3.12 17550% 1.06 175 100%  0.39 200 10% 4.03 200 50% 2.48 200 100%  0.59

TABLE 2 Mass Median Aerodynamic Diameter (MMAD) of Glycerol with 1%Water Temperature MMAD (° C.) Pressure (μm) 100 10% 0.55 100 50% 0.50100 100%  0.89 150 10% 1.80 150 50% 0.47 150 100%  0.45 175 10% 3.27 17550% 0.42 175 100%  0.40 200 10% 4.36 200 50% 1.44 200 100%  —

TABLE 3 Mass Median Aerodynamic Diameter (MMAD) of Glycerol with 2.5%Water Temperature MMAD (° C.) Pressure (μm) 100 10% 0.49 100 50% 0.49100 100%  0.84 150 10% 2.27 150 50% 0.45 150 100%  0.58 175 10% 3.63 17550% 0.43 175 100%  0.42 200 10% 4.47 200 50% 0.49 200 100%  0.48

TABLE 4 Mass Median Aerodynamic Diameter (MMAD) of Glycerol with 5%Water Temperature MMAD (° C.) Pressure (μm) 100 10% 0.48 100 50% 0.52100 100%  0.78 150 10% 2.31 150 50% 0.47 150 100%  0.43 175 10% 3.61 17550% 0.39 175 100%  0.44 200 10% 2.37 200 50% 1.70 200 100%  0.68

Example 2

Using the same experimental setup as described in Example 1, the massmedian aerodynamic diameter (MMAD) was determined on a test medicamentcontaining glycerol, nicotine and water. Results are shown in Tables 5to 8.

TABLE 5 Mass Median Aerodynamic Diameter (MMAD) of Glycerol/Nicotinewith 0.5% Water Temperature MMAD (° C.) Pressure (μm) 100  50% 0.65 100100% 0.67 150  50% 0.41 150 100% 0.48 175  50% 0.43 175 100% 0.44 200 50% 0.39 200 100% 0.43

TABLE 6 Mass Median Aerodynamic Diameter (MMAD) of Glycerol/Nicotinewith 1% Water Temperature MMAD (° C.) Pressure (μm) 100  50% 0.65 100100% 0.81 150  50% 0.41 150 100% 0.50 175  50% 0.44 175 100% 0.40 200 50% 0.51 200 100% 0.39

TABLE 7 Mass Median Aerodynamic Diameter (MMAD) of Glycerol/Nicotinewith 2.5% Water Temperature MMAD (° C.) Pressure (μm) 100  50% 0.67 100100% 1.03 150  50% 0.35 150 100% 0.56 175  50% 0.46 175 100% 0.37 200 50% 0.45 200 100% 0.46

TABLE 8 Mass Median Aerodynamic Diameter (MMAD) of Glycerol/Nicotinewith 5% Water Temperature MMAD (° C.) Pressure (μm) 100  50% 0.64 100100% 1.17 150  50% 0.47 150 100% 0.47 175  50% 0.40 175 100% 0.35 200 50% 0.45 200 100% 0.44

Example 3

Using the same experimental setup as described in Example 1, the massmedian aerodynamic diameter (MMAD) is determined on a test medicamentcontaining glycerol and any one of the active therapeutic agentsdescribed in this application with varying amounts of water.

What is claimed:
 1. A delivery device capable of delivering an inhalablemedicament to a subject, comprising: a housing including a reservoir tapcomprising a conduit; and a cartridge, comprising: a seal positionedadjacent to the reservoir tap when the cartridge is coupled to thehousing; and an inhalable medicament within the cartridge, the reservoirtap selectively operable to penetrate the seal, enabling ejection of theinhalable medicament from the cartridge.
 2. The delivery device of claim1, wherein the seal comprises a self-healing seal.
 3. The deliverydevice of claim 1, wherein the housing further includes an aspirationconduit into which the reservoir tap can eject the inhalable medicament.4. The delivery device of claim 13, wherein the housing further includesa heater associated with the aspiration conduit.
 5. The delivery deviceof claim 1, wherein the reservoir tap slides between a retractedposition and an extended position.
 6. The delivery device of claim 1,wherein, when in the extended position and with the cartridge coupled tothe housing, the reservoir tap extends through the seal of thecartridge, establishing communication between an interior of thecartridge and the conduit of the reservoir tap.
 7. The delivery deviceof claim 1, wherein the cartridge further comprises a porous matrixwithin the reservoir, the liquid medicament residing within pores of theporous matrix.
 8. The delivery device of claim 7, wherein the porousmatrix is located between the seal and the gaseous propellant.
 9. Aninhaled medicament delivery device, comprising: a cartridge including: areservoir including an opening; a seal positioned over the opening ofthe reservoir and sealing the reservoir; and a liquid medicament withinthe reservoir; and a housing with which the cartridge couples,including: an aspiration conduit that receives atomized medicament; anda reservoir tap in communication with the aspiration conduit, thereservoir tap slideable between: a retracted position that, with thecartridge coupled with the housing, is out of contact with the seal ofthe cartridge; and an extended position that, with the cartridge coupledwith the housing, extends through the seal of the cartridge to establishcommunication between the reservoir and the aspiration conduit.
 10. Theinhaled medicament delivery device of claim 9, further comprising: aheater associated with the aspiration conduit.
 11. The inhaledmedicament delivery device of claim 9, wherein reservoir tap includes: abody; a tip at an end of the body; a first conduit extending through thebody, a first port of the first conduit opening to the tip; and a secondconduit extending through the body, a second port of the second conduitopening to a more intermediate location along a length of the body, thereservoir tap having: the retracted position; an intermediate positionbetween the retracted position and the extended position, in which: thefirst port is positionable within the reservoir of the cartridge withthe cartridge coupled to the housing; and the second port is located outof communication with the reservoir with the cartridge coupled to thehousing; and the extended position, in which: the first port ispositionable within the reservoir of the cartridge; and the second portis positionable within the reservoir of the cartridge.
 12. The inhaledmedicament delivery device of claim 11, wherein the second port islarger than the first port.
 13. The inhaled medicament delivery deviceof claim 9, wherein the reservoir of the cartridge comprises a porousmatrix, the liquid medicament being located within pores of the withinthe reservoir.
 14. The inhaled medicament delivery device of claim 13,wherein the porous matrix is located between the gaseous propellant ofthe cartridge and the seal of the cartridge.
 15. The inhaled medicamentdelivery device of claim 9, wherein the seal of the cartridge comprisesa self-healing seal.
 16. A cartridge that stores an inhalablemedicament, comprising: a reservoir with an opening; a seal over theopening of the reservoir, a liquid medicament within the reservoir; anda propellant compressed to an above-ambient pressure to pressurize theliquid medicament within the reservoir.
 17. The cartridge of claim 16,comprising a porous matrix within the reservoir, the liquid medicamentresiding within pores of the porous matrix.
 18. The cartridge of claim17, wherein the porous matrix is located between the seal and thepropellant.
 19. The cartridge of claim 16, wherein the propellant iswithin the reservoir.
 20. The cartridge of claim 16, wherein the sealcomprise a self-healing seal.